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Purinergic Signalling: Therapeutic Developments
Geoffrey Burnstock
Frontiers in Pharmacology · 2017 · Review
Abstract
Purinergic signalling, i.e. the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes 4 subtypes of the P1 (adenosine) receptor, 7 subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventicular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y¬12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y¬12 receptor-mediated platelet aggregation. Diquafasol, a long acting P2Y¬2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes and cancer.
Full text
From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.
Introduction
Purinergic signalling, i.e., nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors, and eight subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. Adenosine 5′-triphosphate (ATP) is a cotransmitter with classical transmitters in both the peripheral and central nervous systems. In addition, purines are powerful extracellular messengers to non-neuronal cells, including secretory, exocrine and endocrine, endothelial, immune, musculo-skeletal and inflammatory cells. Purinergic signalling is rapid in neurotransmission, neuromodulation and in secretion, but is also long-term in proliferation, differentiation, migration and death in development and regeneration.
More recently, the focus has been on the pathophysiology and therapeutic potential of both P1 and P2 receptors. Reviews focussed on different aspects of purinergic pathophysiology are also available, including inflammatory and immune disorders; cancer; gout and fibrosis; P2X7 receptors (R) as therapeutic targets; medicinal chemistry of purinoceptors; pain and adenosine kinase inhibitors. A number of purine-related compounds have been patented. Therapeutic developments for disorders of different systems in the body will now follow. Reviews concerned with the early literature will be quoted, so the focus of this review will be concerned largely with the most recent findings.
Disorders of the Central Nervous System (CNS)
Investigations into purinergic signalling and its roles in disorders of the CNS have been reported, for instance following surgery, stroke, accidents and ischemia, neurodegenerative diseases (such as Parkinson’s, Alzheimer’s and Huntington’s diseases), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), epilepsy and neuropsychiatric disorders (including schizophrenia, depression and anxiety). Reviews covering this topic are available, including the recent attention to the development of centrally penetrant P2X7R antagonists for the treatment of CNS disorders.
Neurodegenerative Diseases
Neurodegeneration in the CNS is associated with inflammation and damage to both neurons and glia. Reviews are available that include coverage of early papers concerned with neurodegenerative diseases. Recent attention has been directed toward the use of P2X7R antagonists for the treatment of neurodegenerative diseases. However, adenosine acting via A2AR has also been claimed as a promising therapeutic agent for the prevention and treatment of neurodegenerative diseases.
Alzheimer’s Disease (AD)
There is progressive cognitive impairment in AD, with prominent deficits in short term memory. The potential of purinergic drugs for the treatment of AD has attracted much interest in recent years. Previous studies have led to the proposal that both P2X7R and P2Y4R antagonists are potential therapeutic targets for the treatment of AD. It has been suggested that the blockade of P2Y1R may have therapeutic potential against cognitive disturbances in AD. β-Amyloid increased release of ATP, which potentiated excitatory synaptic activity via P2XR, effects that were blocked by P2X antagonists. The glycosylphosphatidylinositol-anchored prion protein binds to and modulates the expression of P2X4R, which may be involved in AD. Recently, a potential role has been proposed for ATP-sensitive potassium channel (KATP) modulation as a therapeutic strategy against AD.
Adenosine A3R agonists suppress amyloid-β protein precursor internalisation and amyloid-β generation. Hippocampal adenosine A2AR up-regulation is necessary to trigger memory dysfunction in AD.
Parkinson’s Disease (PD)
The involvement of adenosine A2AR in PD and their interactions with dopamine receptors has attracted most attention (see ). A2AR antagonists have been proposed for the treatment of PD. KATP and P2X1R in PD have also been reported, perhaps indicating new therapeutic targets. Clinical trials istradefylline, an A2AR antagonist, have taken place and it may have a beneficial effect in conjunction with commonly used anti-Parkinson’s therapies, although in a later study, istradefylline was shown to enhance amyloid-β generation and γ-secretase activity. Oligomerisation kinetics of A2A and dopamine D2R have important implications for PD. Clinical trials for A2A antagonists for PD are assessed in a review. A2AR inhibition stopped rotenone-induced motor impairment in a rat model of PD. A1 as well as A2AR antagonists were recommended as promising candidates for treatment of PD in a recent paper.
P2X7R antagonists have also been implicated in this disease. A P2X7R antagonist, brilliant blue G, was recently shown to be protective in a lipopolysaccharide (LPS) animal model of PD.
Huntington’s Disease (HD)
Earlier studies reported that A2AR agonists could be therapeutically useful for HD and that P2X7R antagonists inhibited neuronal apoptosis and attenuated body weight loss and motor co-ordination deficit in HD patients. Adenosine A2AR inhibition reversed working memory deficits of HD at early stages models and it was proposed that A2AR antagonists may therapeutically reverse the cognitive deficits in HD patients. In earlier publications, A1R agonists were suggested to be therapeutic targets. It has been claimed that KATP channels may be potential targets for treatment of HD. Inhibition of equilibrative nucleoside transporter 1 enhances the adenosine level and may be a potential therapeutic approach for treating HD.
Amyotrophic Lateral Sclerosis
Involvement of A2AR, P2X4R and P2X7R in ALS has been reported. A1R have also been implicated in ALS. Preconditioning with latrepirdine, an adenosine 5′-monophosphate (AMP)-activated protein kinase activator, was beneficial in the SOD1 mouse model of ALS. A2AR activation facilitated neuromuscular transmission in SOD1 mice during the pre-symptomatic but not symptomatic phase of the disease. Pharmacological inhibition of A2AR protects against degeneration of spinal motor neurons in the mouse SOD1G93A ALS model.
P2X7R expression was significantly reduced, leading to Ca2+ disturbances in peripheral blood mononuclear cells in ALS patients. Low concentrations of endogenous ATP acting on P2X7R induced motor neuron death. Spinal cord pathology was reduced by P2X7R inhibitors in the mouse SOD1 ALS model.
Multiple Sclerosis
P2X7R and the P2YR-like GPR17 are involved in MS. There is upregulation of ecto-5′-nucleotidase (CD73) in experimental autoimmune encephalomyelitis, which is an MS animal model. Genetic variants in P2X7R affect susceptibility to MS.
Brain Injury
The importance of inflammation in the responses to brain injury has been reviewed and the involvement of P1R and P2R and of P2X7R in particular. The roles of purinergic signalling in neurodegeneration as a consequence of brain injury, neuroprotection and neuroregeneration have been discussed in reviews. Ectonucleotidase activities and nucleotide levels in serum are altered by brain stab injury. P2X7R antagonists appear to be effective as a treatment for radiation injury. Astrocytic p-connexin 43 stimulates neuronic autophagy through P2X7R activation in the hippocampus, resulting in brain injury-induced cognitive deficit repair. P2X7R antagonists have been implicated as a novel target to prevent secondary neurological injury after traumatic brain injury and after spinal cord injury. P2X7R antagonists could be therapeutically effective to treat stroke patients. P2X7R stimulation in acute ischaemic stroke is beneficial by restricting early oedema formation and perhaps by modulating responses of glia. Hypoxic-ischaemic brain injury increases intracellular Ca2+ in oligodendrocytes, which is partly mediated by P2X7R. P2X7R antagonists may provide a new target for the treatment of cerebral ischaemia and for the prevention of ischaemic damage to oligodendrocytes. P2X7 antagonists or inhibition of pannexin-1 channels reduced brain damage following ischaemia.
Activation of upregulated P2Y1R results in neuroblast migration to sites of brain damage. Microglial P2Y12R activation follows neuronal injury. A2AR activation was suggested for the treatment of brain injury and subsequent neuroinflammation. A2AR on cells derived from bone marrow modulate white matter lesions following chronic cerebral hypoperfusion. Diadenosine tetraphosphate (Ap4A) may be a good candidate for traumatic spinal cord injury treatment. Adenosine kinase facilitated astrogliosis after traumatic brain injury and its inhibition in reactive astrocytes ameliorated astrogliosis-induced cell death.
ATP and adenosine concentrations in the brain were significantly raised during brain ischaemia to stimulate P1R and P2R. P2X4R expressed by microglia are involved in post-ischaemic brain inflammation. P2X4R are required for neuroprotection via ischemic preconditioning. Neuronal KATP channels play a role in hypoxic preconditioning where they decrease neonatal hypoxic-ischaemic brain injury; it has been proposed that openers of KATP channels may prove to be therapeutically beneficial. Intranasal administration of guanosine reduced ischaemic brain damage in rats. Ambiguously, both A2AR agonists and antagonists may protect against ischaemic brain injury. A1R contribute to immune responses following neonatal hypoxic ischaemic brain injury. A valuable review of the involvement of P1R, P2XR and P2YR in brain ischemia is available.
Neuroprotection and Neuroregeneration
This topic is explored in recent reviews. Inhibition of P2XR and P2YR as well as activation of P1R following ATP breakdown to adenosine released from CNS cells, have been shown to be neuroprotective. Activation of the pannexin 1/P2X7R complex contribute to the neuroprotection that occurs after ischaemic pre- and post-conditioning. Docosahexaenoic acid in the diet is thought to be a purinergic modulator via P2XR where it protects against neurodegenerative diseases. Neuroprotection mediated by microglia is associated with P2X7R activation and release of tumour necrosis factor-α. Blockade of P2X7R provides neuroprotection against stroke, traumatic brain injury and subarachnoid haemorrhage. P2X7R antagonists improve recovery after spinal cord injury. From a recent study on P2Y2R knockout (KO) mice and murine cell lines, it was concluded that P2Y2R play a neuroprotective role in neurological disorders, especially AD. Neuroprotection is claimed to be mediated by P2Y13 nucleotide receptors in neurons. Activation of P2Y2R evokes regeneration of glial cells and nerves and the P2YR-like GPR17 evokes oligodendrocyte regeneration. Neural stem cell activation leads to neuroregeneration, probably via P2X4R and P2X7R. Reviews focused on the roles played by P2X4R and P2X7R and A2AR in neurodegeneration and neuroprotection have been published.
Psychiatric Disorders
Several antipsychotic drugs (e.g., chlorpromazine, fluspirilene, and haloperidol) were found to antagonise responses mediated by P2XR. These antipsychotic drugs act therapeutically by inhibiting dopaminergic hyperactivity by suppressing P2X-mediated effects (see ). Brain penetrant P2X7R antagonists are being developed as drug targets for psychiatric diseases. Reviews about purinergic signalling in psychiatric disorders, such as addiction, depression, schizophrenia, bipolar disorder and autism, have been previously published. The possibility has been raised that P1R agonists might be beneficial in the therapy of psychiatric disorders.
Schizophrenia
Adenosine neuromodulation in schizophrenia has received the most attention (see;; ). Deletion of A2AR from astrocytes interferes with glutamate homeostasis resulting in cognitive and psychomotor impairment in schizophrenia. It has been suggested that P2X7R and pannexin 1 channels are involved (see; ).
Bipolar Disorder
P2X7R, mediating neuroinflammation via microglial activity, contribute to bipolar disorder (see,; ). Serum concentrations of uric acid increase in different clinical phases of bipolar disorder and in those patients treated with lithium. The purinergic system may become dysregulated during manic episodes and it has been proposed that raised uric acid levels could be a useful indicator of bipolar disorder manic phases. Purinergic modulators that reduce levels of uric acid may be therapeutically beneficial. However, a decrease in serum adenosine levels in bipolar disorder patients was reported.
Depression and Anxiety
Reviews describing the roles of both P1 (A1 and A2A) and P2X7R in mood disorders are available. Antidepressant effects of P2X7 antagonists have been reported. P2X2R in the medial prefrontal cortex mediate the antidepressant-like actions of ATP released from astrocytes. Brilliant blue G, a P2X7R antagonist, had antidepressant and anti-inflammatory actions in mice after LPS administration. The P2X7R antagonist, A-804598, affected neuroimmune and behavioural features of stress. Stress-related mood disorders activate the inflammasome via release of ATP and stimulation of P2X7R. Co-expression of wild-type P2X7R with the polymorphism variant Gln460Arg alters receptor function associated with mood disorders. Increased KATP channel activity due to a mutation led to reduced anxiety in mice. KATP channels are involved in the pathogenesis of depression and may be a therapeutic target for this disorder. Altered levels of several ATP-dependent chromatin remodelling factors may be linked to high trait anxiety.
A2AR antagonists were reported to have antidepressant activity. Creatine and ketamine had antidepressant effects, probably mediated by activation of A1R and A2AR. Caffeine, acting as an A2AR antagonist, prevented depression triggered by chronic stress. Striatal and extrastriatal A2AR in the forebrain regulate fear responses in mice. A2AR mediated increased interleukin (IL)-1β in the brain contributed to anxiety. Fear and anxiety in a mouse model of post-traumatic stress disorder were alleviated by administration of a derivative of adenosine, WS0701. A1R agonists have been used to treat anxiety, but have troublesome side-effects so positive allosteric modulators have been developed as potent anxiolytic agents. An antidepressant-like effect of inosine in mice has been reported.
Autism
Adenosine in addition to suramin, a non-selective ATP antagonist, are reported to improve behaviour in autistic individuals.
Addiction
Targeting A2AR may offer strategies for combating drug addiction. Striatopallidal A2AR signalling in the dorsomedial striatum has been suggested as a therapeutic target in drug addiction by reducing habit formation. Caffeine potentiates the addictive effects of drugs of abuse, including cocaine and amphetamine derivatives.
Treatment of rodents with a P2X3R antagonist diminished opioid tolerance and tolerance to morphine-induced antinociception. Lead-induced neuroinflammation via P2X7R may be responsible for the intensification of morphine tolerance. Opiate-induced changes in brain adenosine levels may be associated with opiate addiction and withdrawal.
Adenosine, acting via A2AR, regulates addiction induced by cocaine. Women are more sensitive to cocaine and are therefore more vulnerable to becoming addicted. Adenosine antagonists may be an effective treatment. A2A-D2 receptor-receptor interactions in the dorsal striatum are differentially affected by cocaine, which contributes to compulsive drug seeking.
Interactions between striatal A2A and glutamate (mGlu5) receptors modulate the drug-seeking effects of methamphetamine. Methamphetamine produces alterations in adenosine receptor expression in the nucleus accumbens. A2AR antagonism in dorsomedial striatum reduces methamphetamine addiction. Adenosine A2AR integrate the rewarding and motivational behaviours of methamphetamine. Behavioural sensitisation provides a model in animals for drug craving that underlies human addiction and sensitisation to amphetamine was reduced by P2Y1R antagonists in the mesocortico-limbic dopaminergic system.
A2AR agonist treatment can help counteract nicotine addiction. A2AR are a potential target for the treatment of alcohol abuse. Regulation in adenosine signalling in striatal circuits in alcohol addiction was reviewed. A1R signalling contributes to the regulation of basolateral amygdala excitability and to the pathophysiology of alcohol addiction. A review of alcohol addiction discusses the role of adenosine. P2X4R modulate synaptic signalling associated with alcohol addiction.
Epilepsy
Early focus was on the role of P1R in epileptic seizures, but P2X4R and P2YR, but especially P2X7R antagonists have been recently explored as neuroleptic agents (see;;;; ). Seizure-induced increases in microglial process numbers were reduced and kainate-induced seizure behaviours were exacerbated in P2Y12 KO mice. Antiepileptic consequences of deep brain stimulation may be mediated by P1R activation. P2X3R expression was upregulated in epileptic rats and humans and it was postulated that P2X3R antagonists might be therapeutically effective. The release of adenosine and ATP during on-going epileptiform activity was measured with microelectrode biosensors. ATP levels were increased during epileptic seizures, which were not of neuronal origin. There is an insightful Editorial about purinergic signalling-induced neuroinflammation in epilepsy.
A role for post-transcriptional control of the P2X7R expression has been proposed and therapeutic targeting of microRNA-22 was suggested to prevent development of epilepsy and inflammation. Purinergic signalling, via P2X7R, regulates neonatal seizures associated with hypophosphatasia, an inherited metabolic bone disease characterised by spontaneous seizures. P2X7R antagonists were effective against hypoxia-induced neonatal seizures in mice.
Migraine
The role of ATP in migraine was initially suggested to involve vascular events (see; ). Later, P2X3R in nociceptive brain areas, including the thalamus and trigeminal nucleus, were investigated and their interaction with P2Y1R in trigeminal neurons. The therapeutic potential of antagonists to P2X7R for migraine treatment has been proposed, as well as P2X3R and P2X2/3R antagonists. Reviews have been published about the roles and therapeutic potential of purinergic signalling in the aetiology of migraine.
Neuropathic Pain
P1R and P2R involvement in neuropathic pain has been discussed in reviews. The discovery by Inoue and colleagues that antagonists to P2X4R on microglia are effective against neuropathic pain was particularly important (see ). Antagonists to P2X7R and P2Y12R also act on microglia to reduce neuropathic pain (see; ). A3R agonists delay the development of neuropathic pain. Glial P2Y2R are potential targets for the management of trigeminal-related pain. Pannexin 1 and P2X7R interactions have been suggested to play a role in chronic pain. P2X7R antagonists have been recommended for the treatment of central post-stroke pain. A review discusses the use of P2XR subtype antagonists for the treatment of central neuropathic pain. Purinergic signalling in the spinal dorsal horn and anterior cingulate cortex appear to be involved in neuropathic pain. P2X3 and P2X2/3R blockade has also been claimed to reduce chronic pain.
Brain Tumours
Neuroblastoma, a rare childhood tumour, expresses P2X7R, which mediate proliferation. The P2X7R appears to be a regulator of neuroblastoma metabolic activity, angiogenesis and growth and may be a target for neuroblastoma treatment. The action of the antitumor agent, temozolomide, was increased by the antiproliferative actions of P2X7R agonists and antagonists to A3R and P2Y1R on human glioblastoma. P2X4R may also be involved in human neuroblastoma.
P2X7R were over-expressed in human malignant gliomas and P2X7R antagonists decreased tumour cell numbers. Extracellular nucleotides control glioma growth via P2X7R and P2Y6R activation. P2X7 and A2AR activation leads to release of cytokines by macrophages, which was prevented by antagonists to these receptors. P2X7R antagonists blocked the cell cytotoxicity caused by irradiation for glioma. Purine nucleoside phosphorylase is released from rat C6 glioma cells, contributing to the purinergic system homeostasis and exhibiting a pathophysiological role.
It was claimed that KATP channels are associated with tumorigenesis of human glioma. A3R blockade enhances the actions of antitumour drugs used against human glioblastoma stem-like cells. A1 and A2BR also sensitise glioblastoma stem cells to chemotherapy. P2Y2R interactions with caveolin-1 represents a novel target for human astrocytoma cells.
Sleep Disorders
P2Y11R appear to be associated with narcolepsy. Reduced endothelial dilation to ATP in cerebral arteries occurred in a rat model of obstructive sleep apnoea. Adenosine is a key player in the regulation and maintenance of sleep-wake dependent neural activity changes, where dysregulation can lead to sleep-wake disorders. The A2AR antagonist, SCH58261, overcame the blood–brain barrier dysfunction as a result of sleep restriction.
Cardiovascular Diseases
Reviews about this topic are available.
Heart Failure
In chronic heart failure adenosine accumulates, probably as a result of lowered adenosine deaminase (ADA) gene expression and raised CD73 activity. Adenosine therapy mediated by A1R and A3R is cardioprotective for chronic heart failure. A1R agonists attenuate cardiac hypertrophy and prevent heart failure in a mouse model (left-ventricular pressure-overload) and in a rat model (neonatal cardiac myocyte). A2BR agonists exert stronger cardioprotective effects against cardiac ischaemia/reperfusion injury compared to A2AR activation in rats. CD73 and A2BR agonists have been considered as therapeutic agents for myocardial ischaemia. Genetic deletion of CD39 results in increased myocardial ischaemia-reperfusion injury. Inflammatory responses initiated during ischemia-mediated immune injury may be regulated by adenosine.
Early studies were concerned with the role of adenosine in ischaemic and reperfusion injuries. However, there is also interest in the role of ATP. Application of ATP, prior to or just after cardiac ischaemia is cardioprotective. ATP released from the ischaemic myocardium causes reflex responses mediated by cardiac sympathetic afferent nerves. P2YR are important therapeutic targets in myocardial protection during ischemia/reperfusion. P2Y6R could be a therapeutic target to regulate cardiac hypertrophy. There is increased expression of P2Y2 and P2X1R in the hearts of rats with congestive heart failure.
P2X4R are needed for neuroprotection via ischemic preconditioning. P2X3R expression increased in dorsal root ganglion (DRG) and superior cervical ganglia neurons, resulting in exaggerated sympathoexcitatory reflexes. NONRATT021972 siRNA decreases the upregulation of P2X7R and improves cardiac function after myocardial ischemia. Mitochondrial KATP channels provide protection against myocardial ischemia/reperfusion injury. KATP channels maintain high energy phosphates and myocardial perfusion in heart failure.
Myocardial Infarction
A clinical trial (Acute Myocardial Infarction Study of Adenosine) concluded that infusion for 3 h of adenosine resulted in a reduction of infarct size. Protection against myocardial infarction was mediated by A1R in the rabbit heart. The A3R agonist IB-MECA produced cardioprotection against myocardial infarction. Microglial P2X7R in the rat hypothalamic paraventricular nuclei regulate the sympathoexcitatory responses in acute myocardial infarction. Loss of mouse P2Y4R protects against myocardial infarction. CD39 reduced infarct size following ischaemia-reperfusion injury. P2Y12R antagonists have been recommended for long-term protection of patients, post-myocardial infarction. The KATP channel opener, natakalim, improves ventricular remodelling of congestive heart failure after myocardial infarction.
Atrial Fibrillation
Adenosine reduces post-operative atrial fibrillation (AF). Up-regulation of A2AR involves abnormal calcium handling in AF. Prevention of A2AR activation in patients with AF may sustain uniform beat-to-beat responses at higher beating frequencies. Adenosine-guided pulmonary vein isolation following a randomised clinical trial was recommended to treat paroxysmal AF, although this has been queried in a more recent clinical trial. ATP-induced AF has also been investigated. The efficacy of the P2Y12 antagonists ticagrelor and prasugrel are not affected in AF. The roles of adenosine and ATP in atrial arrhythmias and fibrillation have been discussed.
Supraventricular Tachycardia
Acute therapy by ATP for paroxysmal supraventricular tachycardia was used in the late 1940’s. In patients with paroxysmal supraventricular tachycardia bolus injection of Adenocard (adenosine) is clinically prescribed to slow conduction time via the atrioventricular node, via A1R. Treatment of paroxysmal supraventricular tachycardia by adenosine and ATP is discussed. To provoke vasovagal reaction in syncope patients ATP and adenosine are administered together with the head-up tilt table test.
Cardiomyopathy
Cardiomyopathy can be an inherited disease, but can occur as a result of vitamin B deficiency, amyloidosis, alcoholism or viral infections. ATP synthase disruption contributes to diabetic cardiomyopathy. P2X7R involvement in dilated cardiomyopathy has been reported.
Cardiac Fibrosis and myocarditis
P2Y11R agonists reduce cardiac fibrosis. Extracellular nucleotide regulation of signalling in cardiac fibrosis has been discussed. The P2X7R antagonist, A740003, reduces experimental autoimmune myocarditis, suggesting a treatment for clinical myocarditis.
Angina
ATP injections to treat angina pectoris associated with coronary disease were used during the 1940s, while AMP was used to treat angina. ATP treatment for patients with coronary insufficiency was also used early. Intracoronary administration of adenosine results in angina pain. Intracoronary administration of adenosine in patients with unstable angina produced decreased myonecrosis and improved coronary blood flow. In vascular pain, which encompasses pelvic and ischaemic pain, migraine and angina, it is thought that release of ATP from endothelial cells during reactive hyperaemia after vasospasm diffuses through the microvascular wall to activate P2X3R on perivascular sensory nerves to send impulses that travel to pain centres in the brain via the spinal cord. P2X2/3R expressed on airway nociceptive sensory nerves mediate cardiovascular reflexes in conscious rats.
Cardiac Transplants
Responses of the transplanted human heart to adenosine show supersensitivity. Protection of cardiac grafts from cold ischaemia/reperfusion injury is caused by donor pretreatment with AMP-activated protein kinase. Treatment with P2XR antagonists prolongs cardiac transplant survival.
Hypertension
It has been proposed in a recent review that there are five different ways that purinergic signalling can contribute to the development of hypertension:
ATP released as a cotransmitter from sympathetic nerves together with noradrenaline (NA) contributes, via P2X1R, to the vasoconstriction that results from increased sympathetic vasomotor activity in hypertension. Therefore, P2X1R antagonists should be useful for the treatment of hypertension, especially since there is a substantial increase in ATP relative to NA released from sympathetic nerves in spontaneously hypertensive rats.
Release of ATP from endothelial cells by shear stress as a result of changes in blood flow acts on P2YR and P2X4R on endothelial cells to release nitric oxide (NO) resulting in vasodilation. Introduction of P2Y1, P2Y2, and P2X4 agonists would cause increased vasodilation in hypertension.
Brain stem and hypothalamic neurons mediate sympathetic nerve activity. Recent studies show that P2X3R antagonists are antihypertensive, due to reduced sympathetic nerve activity as a result of increased peripheral P2X3R-mediated carotid body chemoreceptor reflexes.
P2X7R in the kidney contribute to the pathophysiology of hypertension and P2X7R antagonists may have promise as clinical antihypertensive agents.
In hypertensive patients adenosine activates the vascular renin-angiotensin system. P1R agonists have been suggested for the treatment of hypertension.
Recently, P2Y6R were shown to age-dependently promote vascular remodelling in a mouse model, an effect inhibited by MRS2578, suggesting that P2Y6R are a therapeutic target for the prevention of age-related hypertension.
Atherosclerosis
ATP signalling influences the development of atherosclerosis. Endothelial and smooth muscle cell proliferation are promoted by adenosine and ATP in atherosclerosis via P2Y1, P2Y2, and P1R. In a human model, adenosine, via A2AR, modulates foam cell formation. A2B and A3 antagonists reduce atherosclerotic plaque development. There are increased concentrations of circulating adenosine 5′-diphosphate (ADP) and ATP in atherosclerosis. Uridine 5′-triphosphate (UTP), via P2Y2R, induces expression of vascular cell adhesion molecule-1 in coronary artery endothelial cells, which leads to the monocyte recruitment associated with atherosclerosis development. Upregulated P2Y2R mediate intimal hyperplasia in collared rabbit carotid artery. P2Y1R antagonists are a therapeutic target for neointima formation. Endothelial P2X4R play a more important role in intense proliferation in atherosclerosis than P2Y2R. ATP, by inducing leukocyte recruitment in mice, contributes to atherogenesis, via P2Y2, P2Y6, P2X4, and P2X7R. P2X7R are over-expressed in atherosclerosis and P2X7R deficiency leads to less plaque formation. CD39 mRNA-coated stents may be a treatment for atherosclerosis.
Atherosclerosis of coronary vessels is called coronary artery disease or coronary artery syndrome. P2Y12R antagonists combined with aspirin are beneficial for patients with acute coronary syndrome. A2AR on coronary arteries have also been claimed to be involved in coronary artery disease.
Vascular Injury, Angiogenesis and Restenosis
An initiating event in the pathogenesis of vascular diseases is often vascular injury. Injured cells release ATP, which, together with adenosine, evoke endothelial and smooth muscle cell growth, proliferation, migration and death. Adenosine, following breakdown of ATP, is protective against ischaemic injury. P2Y12R antagonists are prescribed as prevention against ischaemic stroke. P2Y2R mediate regulation of endothelial inflammation and angiogenesis.
Sustained control of proliferation of endothelial and smooth muscle cells as a result of P1 and P2YR activation during vascular remodelling in restenosis after angioplasty has been reported and therapeutic possibilities are being explored. Activation of A2BR stimulates angiogenesis in human microvascular endothelial cells. Adenosine, via A2AR, stimulates wound healing and angiogenesis following tissue injury in mice. CD39 administration decreases injury-induced platelet deposition and recruitment of leukocytes and inhibits neointimal hyperplasia. A review discusses the vascular actions of P2XR in renal injury.
Thrombosis, Inflammation, and Stroke
Nucleotides are extracellular mediators of vascular inflammation and thrombosis. Clopidogrel, a P2Y12 antagonist, inhibits aggregation in platelets and is widely prescribed for thrombosis and stroke. Other P2Y12 antagonists have been developed, including ticlopidine, cangrelor, ticagrelor, prasugrel, elinogrel, BX 667, and PSB 0739. P2Y1R antagonists also have antithrombotic actions and have been recommended as a complement to current P2Y12 anti-platelet strategies. The P2Y6R may be a therapeutic target for systemic inflammatory responses. Review articles are available about purinergic signalling in thrombosis and inflammation, including the use of different oral or intravenous P2Y12R antagonists. P2X7R are pro-thrombotic and genetic KO of the gene for the P2X7R was shown to be protective in a mouse carotid artery thrombosis model. Adenosine, via A2AR and A3R, had antithrombotic effects.
Migraine
Migraine pain involves two distinct cerebrovascular phases: an initial vasoconstriction (with no pain), followed by vasodilation (reactive hyperaemia) associated with pain. A purinergic hypothesis for migraine was proposed in 1981. It was suggested that after the initial vasospasm ATP and adenosine (following breakdown of ATP) may mediate the vasodilation during reactive hyperaemia associated with pain. It was also hypothesised that stimulation of P2X3R on sensory nerve terminals located on the adventitia of the cerebral microvasculature by ATP contributed to the migraine pain. Data has also been presented recently that is consistent with the purinergic hypothesis of migraine pain. P2X3R antagonists have been proposed as potential candidates for migraine treatment. The non-steroidal anti-inflammatory compound, naproxen, currently in use for migraine pain, blocks P2X3R-mediated responses in trigeminal neurons of the rat. Migraine could involve a chronic disorder of the sympathetic nervous system, where increased release of the sympathetic cotransmitter ATP contributes to the initial vasospasm.
Adenosine may also be involved in migraine. Adenosine infusion resulted in symptoms that were migraine-like and withdrawal of the P1R antagonists theophylline and caffeine also resulted in migraine-like symptoms. Clinical trials with the adenosine uptake inhibitor dipyridamole, that results in increased extracellular adenosine, were halted due to the increase of migraine attacks in all patients. Overactive P2YR on glial cells may contribute to pain transduction during migraine. Reviews have been published about the role of purinergic signalling in the aetiology of migraine and the potential of purinergic compounds.
Diabetic Vascular Disease
There is pre-junctional A1R-mediated sympathetic neurotransmission and ATP-mediated endothelial vasodilatation in mesenteric arteries of streptozotocin (STZ) diabetic rats. There is enhanced A2AR-mediated increase in coronary flow in type 1 diabetic mice. UTP, ATP and adenosine evoked vasodilation is reduced in the circulation of skeletal muscle of type 2 diabetic patients. Erythrocyte release of ATP is diminished in type 2 diabetics, supporting the view that a defect in the physiology of erythrocytes may contribute to diabetic vascular disease. Erythrocytes are less deformable in type 2 diabetes leading to lowered levels of deformation-induced ATP release. Low erythrocyte ATP release may contribute to the prevention and treatment of diabetic peripheral vascular disease. P2X7R expression by monocytes might play a role in the pathological changes of type 2 diabetes mellitus.
Aortic Valve Disease
ATP inhibits mineralisation of the aortic valve seen in calcific aortic valve disease. Increased levels of ectonucleotidase are found in calcific aortic valve disease and inhibition of ectonucleotidase with ARL67156 prevented disease development in rats.
Blood Cell Diseases
Adenosine is a potential therapeutic target for the prevention and treatment of sickle cell disease. The circulating levels of adenosine are elevated in pregnant women with sickle cell disease. Amyloid-β peptide inhibits ATP release from erythrocytes, suggesting that in AD, vascular amyloid peptide may play a role.
Diseases of the Airways
Reviews covering the early literature are available.
Inflammation occurs in most diseases of the airways, including chronic obstructive pulmonary disease (COPD), dyspnea, asthma, cystic fibrosis (CF), allergy, infection and injury. Purine nucleotide release from airway epithelial cells is raised in inflammatory processes and has an important role in the pathophysiology of chronic lung disease. P2X7R are a therapeutic target in lung hypersensitivity reactions seen in chronic inflammatory responses. P2X7R modulate lung inflammatory, fibrotic and functional changes in silicosis, an occupational lung disease. P2X4R mediate acute airway inflammation by regulating dendritic cell function. Vagal parasympathetic reflex bronchoconstriction has a role in inflammatory airway disease. Mucin hypersecretion is stimulated in various respiratory diseases and silencing of MUC8 by siRNA increased P2Y2R-induced airway inflammation. P2Y2R have also been claimed to downregulate MUC5AC gene expression. Nucleotides released during airway inflammation activate P2Y6R leading to further release of inflammatory cytokines. Anti-inflammatory effects of adenosine in the lung have been described involving immune cells.
Asthma
A role of adenosine in asthma has been considered for many years, because it is a powerful bronchoconstrictor in asthmatic, but not healthy lungs and P1R antagonists have been used for the treatment of asthma (see ). It was suggested earlier that the bronchoconstriction evoked by adenosine in asthma was as a result of indirect actions by release of leukotrienes, histamine or endothelin (see ). In early reports, A2A, A2B, and A3R were all claimed to mediate inhibition of allergic airway inflammation and mast cells were shown to be involved. Expression of adenosine receptors on monocytes from patients with asthma contributes to the progression of the disease. A2AR are involved in the immunological pathogenesis of asthma.
The roles of nucleotides in asthma has gained attention. In human lung mast cells, ATP is an important modulator of histamine release. Attenuated P2X7R function gives protection from asthma and was suggested to be age related. ATP in sputum was significantly elevated in patients with asthma, which was correlated with the percentage of neutrophils in sputum. Impaired P2X1R-mediated adhesion in eosinophils from asthmatic patients has been reported. P2Y6R activation was effective for treatment of a mouse model of asthma.
In allergic asthma, inhalation of allergens, such as pollen spores or house dust mite allergen, or triggers such as viral infection or air pollution, trigger inflammation. For an immune response to be triggered by allergens, activation of dendritic cells is required. In allergic asthmatics, bronchoconstriction following inhaled adenosine was mediated by A1R. Selective antagonists to A2BR improve inflammatory conditions in allergic asthma. ATP plays a role in inflammation in allergic asthma by recruitment and activation of inflammatory cells. P2Y1R are involved in allergic airway inflammation, probably by regulating maturation of dendritic cells. It has also been proposed that P2Y2R in the respiratory epithelium are important sensors for airborne allergens. P2X7R have been implicated in the pathophysiology of allergy-induced lung inflammation. Activating P2X7R on hematopoietic cells, namely eosinophils or dendritic cells, may be a therapeutic approach to treat allergic asthma. Oxatomide, an anti-allergic antihistamine, is claimed to also act as a P2X7R antagonist. P2R act as modulators of rat eosinophil recruitment in allergic inflammation. Asthmatic patients exhibit hypersensitivity to aerosolised ATP, but the effects of ATP are not mediated by adenosine.
Chronic Obstructive Pulmonary Disease (COPD)
COPD emphysema and chronic bronchitis. COPD is caused by gas or noxious particles, particularly in tobacco smoke, trigging a lung inflammatory response that when in the larger airways is called chronic bronchitis while in the alveoli is called emphysema.
The role of adenosine receptors in COPD has been the main emphasis to date. Combined stimulation of A2B and glucocorticoid receptors in epithelial cells of human airways induces genes that have anti-inflammatory potential for COPD. A2BR on human mast cells were claimed to be a strategic target for COPD and inhaled A2AR agonists have been used for the treatment of COPD. A1, A2B, and A3R antagonists have also been used to treat COPD.
ATP is implicated in COPD as well as adenosine. COPD is characterised by up-regulation of ATP in bronchoalveolar lavage fluid, which promotes inflammation and tissue degradation. ATP-induced pulmonary vasodilation occurs in patients with COPD. Activation of P2X7R signalling by cigarette smoke appears to play a role in the pathogenesis of emphysema. Cigarette smoke induces neutrophil ATP release via P2X7 and probably P2Y2R activation. Aerosolised ATP exacerbates the symptoms of COPD. A valuable review about purinergic signalling and COPD has been published recently.
Airway Infections
Antibiotics, including erythromycin, are used widely for the treatment of lower and upper respiratory tract infections. Erythromycin blocks the P2XR-mediated Ca2+ influx and could represent one mechanism by which it exerts its effects. The airway epithelium has a role in activating the innate immune response during lung bacterial infections to fight the infection. Over-expression of the ectonucleotidase, CD39, promotes bacteria-induced inflammation, mediated largely by P2X7R in mouse airways. It has been proposed that P2X7R agonists together with low molecular weight anti-tuberculosis medicines could be used to treat multi-drug-resistant tuberculosis (TB), although caution was advised as a polymorphism of the P2X7R was reported to increase the risk of recurrence of TB. In infectious inflammatory diseases the roles of P2X7R and ectonucleotidases have been reviewed. Polymorphisms of the P2X7R gene are associated with the prognosis and risk of human TB. Data has been presented to support the view that P2X7R antagonists should be used to treat the aggressive forms of TB. Selective, orally bioavailable and potent ATP synthase inhibitors show activity against both non-replicating and replicating TB. P2X7R contain the spread of Toxoplasma gondii in vivo. The role of purinergic signalling in a mouse model of pneumococcal meningitis has been explored. The authors showed that although P2X7R activated the NLRP3 inflammasome/IL-1β pathway that mediates inflammation in pneumococcal meningitis, neither suramin nor brilliant blue G affected the disease, possibly because of meningitis-associated down-regulation of brain P2X7R expression and/or a decrease in ATP levels in cerebrospinal fluid.
Adenosine protects against Streptococcus pneumoniae infection of the lungs by pulmonary neutrophil recruitment regulation. Macrophages that engulf bacteria produce adenosine that suppresses sensitisation in response to early-life infections. Chemokine release and leukocyte recruitment are modulated by nucleotides in inflamed airways via an action on P2YR on immune and epithelial cells. Mucociliary clearance is the initial defence against infections of the airways. Airway epithelium releases ATP into the surface liquid layer that controls mucus clearance via P2R and, following breakdown to adenosine, also through P1R. Pulmonary TB patients had higher ADA activity in bronchoalveolar lavage fluid and in the sputum.
Infection with the malaria protozoan parasite, Plasmodium falciparum, induces ATP release from erythrocytes. Rupture of erythrocytes releases ATP during the blood-stage of P. chabaudi malaria that increases P2X7R expression on CD4+ T cells. Platelet ADA, CD39, and CD73 expression was reduced in Trypanosoma evansi infected rats. A review about purinergic signalling and malaria-infected erythrocytes is available. Haemolysis produced by leukotoxin, a bacterial virulence factor, was increased by ATP release and P2XR activation of human erythrocytes.
P2X7R activation regulates inflammatory responses during acute viral infection and is involved in the exacerbated immune response seen during influenza virus infection. ATP, released by activated macrophages and damaged cells, modulates lung inflammation in pneumonia in cattle. Both pulmonary microvascular endothelial cells and epithelial cells expressed P2X7R mRNA.
The pneumovirus respiratory syncytial virus commonly causes childhood lower respiratory tract diseases. It reduces alveolar clearance, probably via UTP, released by the bronchoalveolar epithelium following infection, suggesting that P2Y2R antagonists may be therapeutically important for the treatment of severe respiratory syncytial virus bronchiolitis. Rhinoviral stimuli and ATP signalling contribute to human bronchial smooth muscle production of IL-33 by severe asthmatics. ATP is involved in the expression and release of a major airway mucin, MUC5AC, mainly via P2Y2R and it was suggested that modulation of this pathway could be useful clinically for mucus hypersecretion following viral infections.
Lung Injury
Acute respiratory stress syndrome and lung injury can lead to respiratory failure. There is a protective effect of ATP-MgCl2 in ischaemia-reperfusion lung injury. Alveolar macrophages contribute substantially to chronic lung inflammation development, including silicosis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis, and asbestosis.
Alveolar macrophages express P2X7R, which stimulate the IL-1 to IL-5 proinflammatory cytokine cascade and may be clinically relevant in lung hypersensitivity reactions occurring due to chronic inflammation. P2X7R are involved in the pathophysiology of LPS-induced lung injury and LPS-induced inflammation occurs independently of P2Y1R. There is up-regulation of pulmonary P2X4 and P2X7R in both acute and chronic lung injury and P2X7R deletion, but not P2X4 deletion, was lung protective. The initial inflammatory cells recruited during lung injury are pulmonary neutrophils and P2X7R antagonists reduced neutrophil infiltration and proinflammatory cytokine levels.
Neuroendocrine body cells lining the lung epithelium at intervals, release ATP in response to distension, which then stimulates P2X3R to activate vagal sensory fibres that originate in the nodose ganglion. This mechanism may control reflex responses to noxious gases and hyperventilation. Ventilator-induced lung injury may involve ATP release from neuroepithelial cell bodies in response to stretch and therefore may be therapeutically relevant.
Pulmonary fibrosis can be caused by injury. In patients with idiopathic pulmonary fibrosis A2BR signalling may promote the production of inflammatory and fibrotic mediators. Extracellular adenosine levels are closely associated with the progression of pulmonary fibrosis. Adenosine production by CD73 enhanced radiation-induced lung fibrosis. LPS caused increased expression of A1, A2A, and A2B and P2YR, and decreased expression of A3R, while mechanical ventilation reduced P2Y4 mRNA levels. Both A2A and A2BR were claimed to attenuate acute lung injury. Upregulated A2AR activation is likely to improve the healing process after acute LPS-induced lung injury. A protective role for A2BR signalling has been reported to counter ischaemic lung injury. Protective effects of A3R activation in attenuating reperfusion lung injury has also been reported. Inhibition of adenosine kinase attenuates acute lung injury. Inhaled A2BR agonists have been recommended for the treatment of acute lung injury. Adenosine is detrimental in lung recovery following hyperoxic lung injury. Reviews have been written about adenosine receptors as potential therapeutic targets for acute respiratory stress syndrome and acute lung injury.
Cystic Fibrosis (CF)
Cystic fibrosis is hereditary as a result of a loss of function gene mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Some outstanding reviews about purinergic signalling in CF have been published. The regulation of ion transport by UTP and ATP in CF and normal human airway epithelium was proposed early, in retrospect probably via P2Y2 and/or P2Y4R. P2R compounds for the treatment of CF to restore Cl- secretion and/or inhibit Na+ absorption are being investigated. Lipoxin A4, which stops inflammation, is inadequately produced in patients with CF, but it stimulates apical ATP release, which activates P2Y11R resulting in epithelial repair. With the R117H mutation associated with mild forms of CF, there are faults with the gating conformational changes in the CFTR transmembrane domains, although the function of the nucleotide binding domains are unchanged. Gating of the R117H-CFTR was shown to be almost completely rectified by combined treatment with an ATP analogue [N6-(2-phenylethyl)-2′-deoxy-ATP], VX-770 (Ivacaftor, currently used to treat CF) and nitrate ions (NO3-). The authors concluded that future therapeutic developments might include the complementary use of ATP analogues with VX-770.
Cl- secretion across CF airway epithelia is restored by ATP by triggering calcium entry via P2XR. It was suggested that P2X4/6 heteromultimer receptors might be involved. CFTR activity is necessary for ATP release following erythrocyte deformation. CFTR is reduced or absent in CF and mechanical deformation of erythrocytes does not induce ATP release. Increasing nucleotide release via motion could have therapeutic implications for CF patients. Women with CF showed reduced survival compared with males. Oestrogen may lower breathing-induced release of ATP and ATP receptor-mediated [Ca2+]i increase that induces Cl- secretion. Anti-oestrogens may therefore be beneficial in the treatment of CF.
A1R agonists release [Ca2+]i and activate Cl- and K+ currents in CF epithelial cells of the airways. A1 and A2AR participate in regulation of Cl- secretion in CF airway epithelial cells. Bronchoalveolar lavage from CF patients contained high concentrations of adenosine, correlating with higher 5′-nucleotidase and lower ADA activity. Adenosine regulates CFTR via A2BR. The exhaled breath condensate biomarker, adenosine, tracks changes in lung function in CF. There is increased airway adenosine metabolism in early CF.
Lung Cancer
Human lung A549 epithelial-like adenocarcinoma cells express P2UR (i.e., P2Y2 and/or P2Y4) that mediate increases in [Ca2+]i. In A549 cells there is calcium-dependent UTP and ATP release (with subsequent increase in adenosine levels). Erythromycin selectively inhibits influx of Ca2+ induced via P2X4R stimulation in A549 lung tumour cells. A549 cells express P2Y2, P2Y4, and P2Y6, and P2X4R. ATP induces dose-dependent inhibition of growth of cell lines, including human mesothelioma (MER082), human papillary lung adenocarcinoma (H441), human squamous cell lung carcinoma (H520), human large cell lung carcinoma (H460), human small cell lung carcinoma (GLC4) and the PC14 lung adenocarcinoma cell line. ATP was released from Calu-3 cells derived from human lung adenocarcinoma, probably in response to P2Y2R activation. UTP, ATP and uridine diphosphate stimulate proliferation of lung tumour A549 cells through P2Y2 and P2Y6R.
Autocrine ATP release and P2X7R activation affects the migration of human lung cancer cells. A significant increase in survival of non-small cell lung cancer patients with high P2X7R expression was identified compared to patients with low P2X7R expression. Nucleotides released by radiochemotherapy induce chemotaxis, adhesion and proliferation of human lung cancer cells and metastasis was inhibited in immunodeficient mice by purinergic receptor antagonists. An association of P2X7, P2X4, and P2Y1R with distant metastatic lung tumours was observed and increased degradation of ATP and ADP by CD39, which influence tumour growth and metastasisation. ATP promotes cell survival by inducing a long lasting and sustained increase in [Ca2+]i in lung cancer cells. ATP binding cassette E1 promotes growth, invasion and metastasis of lung adenocarcinoma cells. Ecto-5′-nucleotidase (CD73) inhibitors are currently under clinical trial to treat non-small cell lung cancer.
A2BR on host immune cells may participate in promoting angiogenesis and suppressing immunity and A2BR KO mice showed reduced growth in a Lewis lung carcinoma isograft model. ATP increased the cytotoxicity of cisplatin, a common anti-cancer drug for the treatment of lung cancer, in the H460 carcinoma cell line. An A3R agonist inhibited cell proliferation by stopping the cell cycle and by apoptosis in A549 cells. Antagonism of A2AR expressed by lung adenocarcinoma tumour cells inhibited their growth. A2AR expression and CD73 have opposing prognostic effects in non-small cell lung cancer.
Cachexia often occurs in lung cancer patients. In clinical trials, infusion of ATP in advanced non-small cell lung cancer patients contributed beneficially by increasing body weight, muscle strength and quality of life, as well as enhancing survival. ATP has been claimed to reduce radiation-induced damage in patients with non-small cell lung cancer.
Chronic Cough
The therapeutic promise of P2X3R antagonists for the treatment of chronic cough was first recognised by. P2X3R are expressed by airway afferent nerves and mediate hypersensitivity of the cough reflex, which is dramatically reduced by the oral P2X3 antagonist, AF-219. Central A1R were shown to suppress cough.
Pleurisy
Inosine contributed with adenosine to exert, via A2R, anti-inflammatory effects in pleural inflammation.
Lung Allograft
Ecto-5′-nucleotidase (CD73) reduced rejection of airway allografts by stimulating A2AR, which is a negative modulator of lymphocyte recruitment into the allograft. P2X7R antagonists prolong mouse lung allograft survival.
Diseases of the Special Senses
Purinergic signalling is involved in the physiology of the nasal organs, ear, eye and tongue. Purinergic drugs are being explored for corneal injury, retinal detachment, glaucoma, dry eye, retinitis, uveitis, rhinosinusitis, diabetic retinopathy, macular degeneration, noxious odour damage, Ménière’s disease, sensorineural deafness, tinnitus and taste defects.
Eye
The early literature up to 2006 was reviewed and there are more recent reviews covering the treatment of ocular diseases by purinergic drugs.
Glaucoma is characterised by progressive degeneration of retinal ganglion cells and visual loss. Elevated intraocular pressure reduction is the treatable risk factor for glaucoma. P2X7R antagonists are being explored for the treatment of glaucoma. There is elevation of extracellular ATP and upregulation of NTPDase1 in animal models of chronic glaucoma. Cromakalim, a KATP channel opener, lowers intraocular pressure. Evidence for the use of adenosine receptor antagonists for the treatment of glaucoma has also been presented. Ap4A improves adrenergic anti-glaucomatous therapeutic effectiveness and has recently been claimed to be an effective compound for the treatment of glaucoma.
Treatment for dry eye by a long lasting P2Y2R agonist, diquafosol, was developed by Inspire Pharmaceuticals, Inc. and is currently in use in Japan and Korea (see ).
A P2Y2R agonist, INS37217, enhances subretinal fluid reabsorption and is recommended for the treatment of retinal detachment.
P2X7R antagonist and A3R agonists have been implicated for the treatment of diabetic neuropathy and retinopathy, photoreceptor neurodegeneration, retinitis and uveitis.
The roles of P2Y2 and P2X7R in corneal wound healing have been reviewed. P2X7R activation in oxysterol cytotoxicity may be a target for the treatment of age-related macular degeneration.
Ear
In the auditory system ATP depressed sound-evoked action potentials in the auditory nerve by stimulating P2YR. Acoustic over-stimulation can cause permanent hearing loss due to damage and death of cochlea hair cells. Noise exposure promotes the release of ATP into endolymph. ATP regulates hearing sensitivity and could be useful to treat sensorineural deafness, Ménières disease and tinnitus. UTP infusion into the deafened guinea pig inner ear rescued auditory neurons. P2XR-mediated control of cochlear gap junctions may be protective by reducing hearing sensitivity to noise stress, perhaps via P2X2R. Susceptibility to hearing loss and noise-induced neural injury in the mouse cochlea is regulated by A2AR.
Olfactory Organs
Purinergic receptors are expressed in the nasal mucosa, including P2X3R on olfactory neurons. There is enhanced odour sensitivity in the presence of antagonists to P2R suggesting that endogenous ATP at a low level normally decreases odour responsiveness. Chemosensory trigeminal neurons express P2X2R, which contribute to control of odour recognition. Activation of P2X3R negatively modulates the odour response, indicating a protective strategy for olfactory sensory neurons. Olfactory nerves and secretory cells in the vomeronasal organ express purinoceptors. Heat-shock protein induction by noxious odour damage is inhibited by P2R antagonists in vivo. The inhibitory effect of ATP in odour responses may contribute to the reduction of odour sensitivity following exposure to noxious fumes and could be a new mechanism for neuroprotection. ATP release following injury leads to post-injury neuroregeneration and may result in the development of therapies to restore loss of smell. P2Y1R increase neuronal network activity in the developing olfactory bulb. Purinergic signalling serves as a paracrine signal in regulating the neurogenesis of mouse olfactory epithelium. It has been claimed that purinoceptors are a therapeutic target to alleviate or restore loss of olfactory sensory neurons by the mycotoxin, satratoxin. Activation of A2R may be a novel therapeutic approach for enhancing nasal mucociliary clearance in chronic rhinosinusitis.
Tongue
ATP is a key neurotransmitter in the taste system, acting largely via P2X2/3 heteromultimer receptors. Consequently, disruption of taste function may be an unintentional consequence of therapeutic trials of pain, chronic cough and other conditions using purinergic P2X3R antagonists.
Immune System and Inflammation
P2X7, P2Y1, and P2Y2R on immune and inflammatory cells are important in immunomodulation and inflammation, and the purinergic contribution to neuroinflammation underlying neuropathology has been discussed in several recent reviews. The role of P2X7R in particular in diseases related to neuroinflammation and the use of P2X7R centrally penetrant antagonists has been highlighted. It has been claimed that activation of P2X1R on neutrophils and platelets is involved in regulation of thrombo-inflammation. P2Y12R activation modulates sepsis-induced inflammation. Adenosine, acting mainly via A2AR, is also involved in neoplastic and inflammatory and immune-mediated disease states.
Infection
Reviews have been published concerned with purinergic signalling in immune cell trafficking at sites of infection and P2X7R in infectious inflammatory diseases. Apoptosis of macrophages via ATP-stimulated P2X7R leads to the killing of the mycobacteria they contain, which may lead to new strategies to combat bacterial infections. The cytotoxic effects of ATP on macrophages are through P2X7R, while the bactericidal actions of ATP (and UTP) may be though P2Y2R. There is a valuable article about purinergic signalling in infection and autoimmune diseases. The P2X7R is a potential target for the treatment of Clostridium perfringens type C infection. P2X7R activation modulates cell death during Porphyromonas gingivalis infection. P2X7 and P2X4R activation is protective during severe Escherichia coli infection. P2X7R develop the inflammatory response associated with sepsis and might serve as a therapeutic target to ameliorate brain damage in sepsis. A2AR have also been recommended as a therapeutic target to treat sepsis. The role of purinergic signalling in the immune response in sepsis has been reviewed. ATP protects against sepsis through P2X7R on macrophages by enhancing intracellular bacterial killing. Chlamydiae are intracellular bacterial pathogens and these infections are influenced by inflammasomes and purinergic signalling. Purines modulate the inflammatory response in rats infected by Cryptococcus neoformans. ADP facilitates monocyte recruitment in bacterial infection. ATP synthase has been proposed as a target to kill Mycobacterium tuberculosis. Purinergic enzymatic activities in lymphocytes and cardiomyocytes modulated the inflammatory responses of mice infected by T. cruzi. Adenosine restored LPS-inhibited chemotaxis via A1R, making this a promising therapeutic strategy for infectious diseases.
Infection by Schistosoma mansoni, a parasitic blood fluke, results in thymic atrophy. The cloning and characterisation of a P2XR (schP2X) from S. mansoni was the first non-vertebrate ATP-gated ion channel, which could be an alternative drug target to treat schistosomiasis (see ). Purinergic signalling influences the immune response to infection by Leishmania, a protozoan parasite. Purinergic signalling is involved in Trichomonas vaginalis parasite infection. The dysfunction of P1, P2Y and P2X7R and NTPDases are likely to contribute to morbidity due to human schistosomiasis. P2X7R are important in parasite control as they regulate T effector cells and inflammation during L. amazonensis infection. A commentary about ATP as an initiator of immunity to parasitic infections has been published.
P2X7R modulate the antiviral and inflammatory processes that occur during Dengue virus-2 infection and exacerbate the immune response that occurs during influenza virus infection. P2X4R antagonists reduce herpetic pain. Both P2X4 and P2X7R are involved in hepatitis C virus infection. Purinoceptors are putative targets for the treatment of HIV-1 infection. Ribavirin, an adenosine analogue, exhibited potent antiviral activities.
Endocrine Diseases
Purinoceptors are expressed widely by endocrine glands. Actions of purines have been described in the pituitary gland, with implications for pathological as well as physiological states. 5′-Nucleotidase activity in platelets is changed by hyper- and hypothyroidism and could be a further mechanism by which alterations in thyroid hormones are related to vascular diseases. The role of purinergic signalling in thyroid hormone activities in health and disease has been reviewed. In the ovary, follicular atresia involves cellular degeneration that is due to apoptosis evoked by P2X7R activation in both somatic and germinal follicular cells. Adiponectin, secreted by adipocytes, is anti-inflammatory, protecting against fatty liver disorder, insulin-resistant type 2 diabetes and atherosclerosis. A review including the limited knowledge of purinergic signalling in the endocrine system has been published.
Diabetes
Fibroblast P2YR are impaired in type 2 diabetes, which leads to lower glucose uptake, indicating that P2YR could be therapeutically useful as antidiabetic drugs. Analogues of the P2Y1R agonist, 2-methylthio ADP, have been developed for the treatment of type 2 diabetes. P2YR activation potentiates insulin secretion making it a promising therapeutic target for type 2 diabetes. Adenosine, acting via A2AR, increases pancreatic β-cell proliferation, and has been suggested as a therapeutic target for diabetes. Uridine adenosine tetraphosphate may be a therapeutic target for diabetes.
There is an enhancement of P2X7R-induced apoptosis on the retinal microvasculature in early diabetes. P2X7R located on glucagon-containing α cells in pancreatic islets in STZ-induced diabetic animals increase and they migrate centrally to replace missing insulin-containing β cells. P2X7R antagonists have been proposed as a therapeutic target to cause immunosuppression and tolerance induction in pancreatic islet transplantation. NONRATT021972 siRNA decreases the expression of P2X7 mRNA and protein in DRG, reducing mechanical and thermal hyperalgesia in type 2 diabetic rats (c). Type 1 diabetes impairs P2X7R signalling in osteocytes that affects osteoblast function and maintenance of bone health. STZ-induced type 1 diabetes was prevented in P2X7R KO mice. Diabetic sympathetic neuropathy in type 2 diabetic rats was reduced by decreasing the expression of P2X7R in superior cervical ganglia. P2X7R are expressed in pancreatic cancer cells. P2X7R antagonists are likely to be effective therapeutic agents.
P2X3R antagonists have been proposed for the treatment of diabetic neuropathic pain. Recently P2X7R have also been claimed to be involved in painful diabetic neuropathy in rats. P2X7R polymorphisms are associated with severe diabetic neuropathic pain scores. A1R agonists improve mechanical allodynia in a painful diabetic neuropathy mouse model.
There is up-regulation of hippocampal A2AR in STZ-diabetes and A2AR antagonists gave neuroprotection. A2AR are a therapeutic target for diabetic retinopathy. Reduced expression of A1R in pancreatic α-cells could result in the development of type 1 diabetes. There is increased expression of A2BR in women with gestational diabetes mellitus. In diabetic rats, A2BR agonists improve erectile function. It was suggested that reduction in A3R expression/function may slow the progression of diabetic neuropathy. Blockade of ATP synthase interaction with cyclophilin D has been proposed as a promising therapeutic target to treat diabetic encephalopathy.
KATP channels have neuroprotective effects in patients with type 2 diabetes. P2Y1 and P2Y2R mediate relaxation of the rat corpus cavernosum and may improve erectile function in men with diabetes.
An A2AR agonist was shown to enhance healing of chronic diabetic foot ulcers in a clinical trial. Adenosine kinase inhibitors attenuate inflammation in diabetic retinopathy. Retinal inflammation in diabetic retinopathy is mediated by ADA2 and the anti-inflammatory activity of A2AR signalling is impaired with increased ADA2 activity.
Several reviews about purinergic signalling in diabetes and its therapeutic potential are available. The involvement of purinergic signalling in diabetic nephropathy is discussed later in the Section on Kidney.
Obesity
ATP released as a cotransmitter from sympathetic nerves, stimulates brown adipocytes. ATP stimulates lipogenesis in rat adipocytes, regulating fat stores not via established hormones. Adipocytes express two different P2YR subtypes and P2Y11R activation inhibited insulin-stimulated lepton production and lipolysis stimulation. P2Y4R mediate inhibition of cardiac fat formation. The anti-obesity effects of sesamol, a potent anti-inflammatory compound, is mediated by AMP-activated protein kinase. Blocking P2Y6R activation in the CNS with the antagonist MRS2578 inhibits feeding in mice.
Some ATP effects are as a result of adenosine, after breakdown of ATP, which is also involved in the activities of adipocytes. Adenosine increased lipolysis and induced thermogenesis in brown adipocytes via A2AR. They showed that A2AR antagonists counteract high fat-induced obesity in mice. Administration of A2AR agonists to obese mice caused improvements in glucose homeostasis and adipose tissue inflammation, suggesting that this may show promise for therapeutic treatment of obesity.
There is disturbance of adiponectin secretion in obese patients and adiponectin release is controlled by ATP. A combination of Ca2+ and ATP augments vesicular release of adiponectin. Both ATP and adenosine have roles in the regulation of leptin secretion from adipocytes. There is abnormal fat distribution in P2X7R KO mice. Manipulation of P2XR signalling may represent a novel therapeutic target in metabolically unhealthy obesity under inflammatory conditions. There is protection of rats on high fat diet by adenosine. Perivascular adipose tissue of heavy smokers has increased expression of P2X7R and inflammasome components leading to increased release of inflammatory cytokines.
Gut Disorders
Purinergic signalling plays an important role in a variety of gut activities. ATP is a cotransmitter in non-adrenergic, non-cholinergic inhibitory nerves involved in peristalsis, a synaptic transmitter in submucosal and myenteric ganglia, it mediates mucosal secretion and vascular control of the gastrointestinal tract. Both interstitial cells of Cajal and enteric glial cells express P2R.
Investigations of purinoceptors as therapeutic candidates for gut disorders are underway.
Inflammatory Bowel Disease (IBD)
Nucleotides and their receptors are involved in the pathogenesis of IBD, of which ulcerative colitis (UC) and Crohn’s disease are the main types. P2Y6R are highly expressed on the T cells infiltrating IBD, suggesting that P2Y6R may play a role in the pathogenesis of IBD. P2X7R agonists are involved in colonic motor dysfunction associated with bowel inflammation in rats and are over-expressed in gut mucosa of patients with IBD. P2X7R KO mice are protected against gut inflammation. ATP activates mast cells, which further promote the inflammatory process. Oestrogen receptor β activation plays a therapeutic role in IBD by down-regulation of P2X3 and P2X7R. The roles of P2X7R in IBD are discussed in reviews.
P2X7R-expressing enteric neurons are differentially affected in UC based on their chemical codes. In a later paper, it was shown that UC affected secretory and vasodilatory neurons, enteric sensory neurons and enteric glia of the submucosal plexus expressing P2X7R. The P2X7R antagonist, A438079, down-regulated the production of proinflammatory cytokines and attenuated murine colitis, indicating that P2X7R mediate inflammatory responses during UC. Activation of P2X7R triggers the death of mucosal regulatory T cells. There was P2XR enhancement in an animal model of UC. MicroRNA-16 and microRNA-206 have pro-inflammatory roles in UC by down-regulating A2A and A3R expression.
There is increased expression of P2X7R in the inflamed mucosa in Crohn’s disease, suggesting that P2X7R antagonists may be targets for treatment of Crohn’s disease. P2X3R antagonists are being explored as therapeutic agents against colic and UC pain, as well as antibodies against P2X3R.
The potential of P2X3R to treat irritable bowel syndrome has been suggested. In diarrhoea-predominant irritable bowel syndrome there is increased expression of P2Y1 and P2Y2R, which was associated with abdominal pain. P2X7R in DRG play a role in transmission of the nociceptive signal from the gut. A review about purinergic mediators in the control of intestinal inflammation and irritable bowel syndrome is available.
Motility Disorders
Purinergic signalling is involved in gastrointestinal motility disorders, including diarrhoea and constipation. Purinergic fast inhibitory junction potentials are impaired in Hirschsprung’s disease. P2X4 and P2X7R activity was potentiated in enteric glia isolated from mice treated long-term with morphine.
A review focuses on the pathophysiological roles of P2YR in inflammation. Aged mice have a lower ability to deal with inflammation evoked by Candida albicans infection, due to a lower gut density of A2AR, which reduce inflammation.
Colorectal Cancer
Apoptosis is induced by extracellular ATP and ATP also reduced growth of primary cultures of colorectal carcinomas, possibly via P2Y2R (see; ). Purinergic responses of HT-29 cells, a colonic adenocarcinoma cell line, are mediated by P2Y2 and/or P2Y4R. Enhanced expression of A2BR on colorectal cancer cells that are proliferating suggests that antagonists to A2BR may be a promising therapeutic target for colorectal cancer. 8-Chloro adenosine inhibited growth of colorectal cancer cell lines 80514 and HCT116 in vivo and in vitro. A phase II, multi-centre study of CF101, an A3R agonist, showed stabilisation of tumour in 35% of refractory metastatic colorectal cancer patients. P2X7R antagonists reduce tumour occurrence in a colitis-associated cancer mouse model. There is high expression of the ectonucleotidase CD39 in human rectal adenocarcinoma.
Diseases of the Kidney
Reviews are available, including one that focuses on the roles played by ATP released as a cotransmitter from sympathetic nerves in renal diseases.
Purinoceptors are richly expressed in the glomerulus, renal vascular system and nephron in the kidney, including subtypes involved in the regulation of glomerular filtration, renin secretion and transport of nutrients, ions, water and toxins. The distribution of NTPDases 1 and 2 parallels the distribution of P2R in the kidney, influencing physiological and pathophysiological renal events (see ). Adenosine and ATP have protective effects against renal ischaemic-reperfusion injury, and have been investigated for transplantation-induced erythrocytosis and chronic renal failure treatment. It has been suggested that nephron luminal P2R are part of an epithelial ‘secretory’ defence mechanism against harmful particles or bacteria. Increased expression of P2X7R in glomerulonephritis, hypertension, polycystic kidney disease (PKD) and diabetes may be therapeutically relevant as a novel treatment of kidney failure.
Renal Injury and Failure
ATP contributes to kidney remodelling and progression toward chronic renal failure (with associated sympathetic overactivity). P2X7R are expressed weakly in healthy glomerulus, but after glomerular injury (e.g., in hypertension and diabetes) are upregulated, mostly in podocytes, but also in mesangial and endothelial cells. P2X7R play a role in altered intracellular calcium homeostasis in peripheral blood mononuclear cells of chronic kidney disease patients. P2X7R mediate deleterious renal epithelial-fibroblast cross-talk. P2X7R antagonists may be therapeutic targets to prevent and treat morbidity and mortality in kidney injury. P2X7R antagonists were protective against ischaemic acute kidney injury in mice. Arterial calcification is a feature in chronic kidney disease patients and ATP signalling is involved (see ). Cyclosporine is a potent immunosuppressive agent, but with limitations because of its side effect of nephrotoxicity. However, treatment with ATP following pre-treatment with verapamil greatly reduces nephrotoxicity. ATP is an important contributor to innate immunity regulation in primary idiopathic nephrotic syndrome. There is increased renal fibrosis in P2X4R-deficient mice following unilateral ureteric obstruction.
Adenosine mediates haemodynamic changes in adult renal failure. A2BR-mediated IL-6 induction contributes to renal fibrogenesis and this receptor has therapeutic potential for treatment of chronic kidney disease. Dendritic cells and macrophages activated by A2AR agonists attenuate acute renal injury. There is a review describing A2AR in acute kidney injury.
Polycystic Kidney Disease (PKD)
The genetic disorder PKD results in abnormal proliferation of tubular cells of the adult nephron, leading to progressive dilation of tubules and formation of fluid-filled cysts that destroy by compression neighbouring tissue. In the cysts ATP is released at high concentrations. The Caenorhabditis elegans nematode is an animal model for investigating basic molecular mechanisms underlying human autosomal dominant PKD; the C. elegans PKD-2 and LOV-1 proteins are homologues of human polycystin (PC)-1 and PC-2 proteins. Nucleotide release is involved in both fluid flow and pressure responses and its role in altered mechanosensory transduction in PKD is considered in a review.
Cysts in the collecting ducts of the cpk/cpk mouse model of congenital PKD express P2X7R, where they mediate cyst development. P2Y1, P2Y2, P2Y4, P2Y6, P2X5, and P2X7R were found on the lining epithelial cells of renal cysts in the rat Han:SPRD cy/+ model of autosomal dominant PKD. Expression of mRNA and protein for P2Y2, P2Y6, and P2X7R increased substantially as the disease developed. ATP inhibits renal cyst growth, via P2X7R. The P2X7R antagonists, oxidised ATP and A-438079, reduced cyst formation via extracellular signal-regulated kinase-dependent pathways in a zebrafish model of PKD. Nucleotides in the lumen fluid of cysts stimulate P2YR resulting in increased growth of Madin Darby canine kidney-derived cysts. Knocking out PKD-1 gene expression increased A3R in human renal cells. There is a review about the functional and therapeutic importance of purinergic signalling in PKD.
Ischaemia
Proximal tubular ATP declines rapidly in ischaemic acute renal failure. There was early recognition that there was restoration after ischaemia by perfusion of ATP-MgCl2 and A3R KO mice were shown to be protected against ischaemic renal failure. The ectonucleotidase CD73 protects the kidney from ischaemia-reperfusion injury via production of adenosine and free radical reduction. The role of adenosine in protection from renal ischaemia-reperfusion injury has been investigated and discussed in reviews.
Nephritis
Glomerulonephritis is one of the leading causes of end-stage renal disease. Increased expression of pro-apoptotic P2X7R has been demonstrated in both experimental and human glomerulonephritis, which suggests that P2X7R antagonists may have therapeutic potential. It was shown later that P2X7R-deficiency attenuated renal injury in experimental glomerulonephritis. P2X7R blockade attenuates lupus nephritis by inhibiting inflammasome activation and protects against cisplatin-induced nephrotoxicity. The P2R antagonist, pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate (PPADS), effectively inhibits mesangial cell proliferation in a rat mesangial proliferative glomerulonephritis model. Tubuloglomerular feedback is greatly reduced in Thy-1 nephritic rats, but exogenous 5′-nucleotidase improved it. In P2Y1R KO mice, there is protection against fibrosis and death by renal failure as a result of experimental crescentic glomerulonephritis. Adenosine uptake inhibitors attenuated glomerulonephritis in mice. A2AR agonists may treat macrophage-mediated experimental glomerulonephritis. A2AR agonists reduced inflammation in mouse kidneys, suggesting a therapeutic approach for human lupus nephritis.
Hypertension
Hypertension is a feature of chronic renal disease; this is due largely to sympathetic overactivity as a result of afferent signals from the kidney and triggering sympathetic tone resetting by activation of hypothalamic centres. ATP is a cotransmitter released from sympathetic nerves, whose activity is increased in hypertension.
There is an enhanced P2R-mediated vasoconstriction of both efferent and afferent arterioles in chronic angiotensin II-induced hypertensive rats, with predominant P2X1 and P2X7R control of glomerular haemodynamics. In connexin 30 KO mice, epithelial sodium channels that are unable to respond to changes in sodium levels as a result of reduced paracrine ATP feedback regulation may play a role in salt-sensitive hypertension. Mice lacking P2Y2R have salt-resistant hypertension. The P2X7R is expressed weakly in healthy kidney glomerulus, but expression is significantly increased in hypertension. P2X7R antagonists inhibited the development of renal injury and salt-sensitive hypertension in Dahl salt-sensitive rats. Activation of A1R in mouse proximal tubules, modulated deoxycorticosterone acetate-salt hypertension.
Diabetic Nephropathy
Adenosine receptor agonists protect STZ-diabetic rats from nephropathy. A review discusses the role of A2BR antagonists as therapeutic treatment of diabetic nephropathy. CD73 generation of adenosine attenuates diabetic nephropathy. A3R antagonists reduced fibrosis in diabetic nephropathy. AMP-activated protein kinase has been proposed as a potential treatment of diabetic nephropathy. Chronic A2AR stimulation prevents proteinuria and glomerular damage in experimental diabetes.
P2X7R agonists evoke renal inflammation and injury induced by high-fat diet in type 2 diabetes, suggesting that P2X7R antagonists might be of therapeutic interest. P2X7R expression was increased in the STZ diabetic rat model. It has been suggested that P2X7R antagonists may be a useful coadjuvant treatment to delay the progression of diabetic nephropathy. Data has been presented to suggest that activation of P2X7R contributes to the high prevalence of kidney disease found in diabetics. Deletion of the P2Y2R reduced the development of nephrogenic diabetes insipidus polyuria induced by lithium. Blockade of P2Y12R in the renal collecting duct alleviates nephrogenic diabetes insipidus.
Nephrotoxicant Injury
Drug-induced nephrotoxicity was reduced by ATP-MgCl2. A1R antagonists are protective against cisplatin-induced acute kidney injury in rats. Adenosine antagonists are protective against acute renal failure. A1R antagonists also reduce nephrotoxicity induced by the immunosuppressive agent cyclosporine. Cyclosporine increases plasma adenosine levels in kidney transplant patients. A3R antagonism is effective against acute tacrolimus toxicity.
Cancer
P2X7R are strongly expressed on human embryonic kidney tumours, associated with increased proliferation. The anthraquinone, emodin, inhibits human embryonic kidney cancer cell invasiveness by antagonising P2X7R. A prognostic indicator for post-operative cancer-specific survival of clear-cell renal cell carcinoma patients is P2X7R expression.
Diseases of the Lower Urinary Tract
The early literature has been thoroughly reviewed.
Urinary Bladder
In contrast to laboratory animals, where the purinergic component of bladder parasympathetic cotransmission is about 50%, in healthy human bladder it is approximately 2% although ATP receptors are expressed by the smooth muscle. In pathological conditions, however, such as neurogenic bladder, outflow obstruction and interstitial cystitis (IC), the purinergic component can be as much as 40% and is consequently a therapeutic target. Botulinum neurotoxin type A (BTXA) is often used to treat bladder incontinence, where it inhibits ATP release as well as acetylcholine (ACh) release both from parasympathetic nerves and urothelial cells. Bladder epithelial cell release of ATP from patients with IC was substantially higher compared to healthy controls. Dysfunction in micturition involves P2X3R in rats with chronic spinal cord-injury, suggesting that P2X3R antagonists could be used to treat neurogenic bladder dysfunction.
Overactive Bladder (OAB) Syndrome
There are valuable reviews that discuss the roles of purinergic signalling in OAB. OAB syndrome, which increases in old age, is characterised by frequency, nocturia and urgency, with or without urge incontinence. Women with an OAB exhibit higher ATP levels in their urine compared to controls, suggesting that this could be used as a prognostic marker for detrusor overactivity. The increased urine ATP concentration is due to increased release of ATP from proliferating urothelium and reduced metabolism of ATP. P2X3R are present in the human bladder and, when upregulated, may play a role in the pathophysiology of OAB.
Patients with metabolic syndrome, where the risk of developing cardiovascular disease and diabetes is increased, exhibit a higher incidence of OAB. P2X3R expression is increased in subepithelial sensory nerves resulting in increased bladder activity. OAB is common among PD patients and inhibition of overactivity by A2AR antagonists occurs, probably by acting in the CNS to regulate the micturition reflex. Uridine diphosphate via P2Y6R regulates abnormal smooth muscle activity in the OAB and increases contractions due to P2X1R activation. P2Y6-deficiency increases micturition frequency and reduces contractility in the mouse urinary bladder.
Unstable Bladder
Unstable bladder (also referred to as detrusor instability or detrusor hyperreflexia) is either neurogenic or idiopathic in origin. Neurogenic detrusor instability can occur as a result of a stroke, or pelvic or spinal cord injury, as well as in PD and MS. Neurogenic bladders are hyper-responsive to ATP, via P2X3R.
Expression of P2X2R in both urothelium and detrusor muscle of suprasacral spinal cord injury patients are similar to P2X2R expression in bladder tissue from idiopathic overactive bladder patients. ATP levels increased in the rat spinal cord-injured bladder that activates P2X3 and P2X2/3R on afferent nerve fibres resulting in neurogenic bladder overactivity. P2YR agonists ADP, UTP and uridine diphosphate originating in the urothelium augment the contractile overactivity following spinal cord injury. Sympathetic nerve hyperactivity may play a role in reflex sympathetic dystrophy where increased ATP would be released as a cotransmitter to activate P2X1R on smooth muscle resulting in increased contractions of the bladder and P2X3R on sensory nerve fibre terminals resulting in bladder reflexes and nociception. Inhibition of P2X7R expressed at spinal cord injury sites improved the dysfunction of neurogenic bladder.
Urothelial cell ATP release (both resting and evoked) was substantially more from rat bladders following chronic spinal cord injury, contributing to bladder hyperactivity development. In a mouse bladder overactivity model, bradykinin facilitated the release of ATP from nerve terminals via prejunctional receptors.
In the absence of P2X3R in KO mice, there is bladder hyperactivity. AF-219, a P2X3 and P2X2/3R antagonist that is metabolically stable and orally bioavailable, is being investigated as a treatment for urinary tract dysfunction.
Idiopathic detrusor instability patients show abnormal bladder purinergic transmission, which may contribute to the symptoms of OAB. There is greater potency of ATP via P2X1R for generating detrusor contractions in unstable bladder patients. Urothelial release of ATP from human bladders from patients with detrusor overactivity occurs in both idiopathic and neurogenic conditions. Oxybutynin, administered chronically, results in a shift from muscarinic to purinergic transmission in the rat bladder wall. Expression of P2X3R is increased on suburothelial sensory nerve fibres in idiopathic detrusor overactivity patients.
Interstitial Cystitis (IC)/Bladder Pain Syndrome
The possible roles of ATP and adenosine in IC/bladder pain syndrome are discussed in a review. Hypoosmotic mechanical stimulation of urothelial cells released ATP that was substantially increased in cyclophosphamide-induced inflamed bladder. In rats with cystitis induced by hydrochloric acid, purinergic receptors were lost, although release of ATP from mucosal cells was increased.
Contractions of the rat bladder mediated by parasympathetic nerve stimulation and release of ATP and ACh, were reduced in cyclophosphamide-induced cystitis, while P2XR function in sensory neurons was enhanced. The purinergic component was abolished in the neurogenic bladder following desensitisation with α,β-methylene ATP (α,β-meATP). ATP release due to stretch from bladder urothelium from IC patients was greater compared to healthy urothelium and P2X3R expression was upregulated. Urothelial cells from cats with feline IC responded to α,β-meATP, indicating increased expression of urothelial P2XR. There is mechanical hypersensitivity of the bladder in feline IC together with greater release of ATP from the urothelium; P2X1R expression is reduced and P2Y2R expression is lost.
A1R blockade during the initial phase of IC/bladder pain syndrome was suggested as a treatment for this condition. The A1R in rat urinary bladder is decreased in cyclophosphamide-induced cystitis.
In neutrophils and macrophages in the submucosa of the bladder from mice with cyclophosphamide-induced haemorrhagic cystitis, expression of P2X7R is increased. Treatment with A-438079, a P2X7R antagonist, or genetic ablation of this receptor reduced nociceptive behaviour.
Outflow Obstruction
P2X1R expression in smooth muscle of the bladder was increased in the human obstructed bladder. In animal models of outlet obstruction, in vivo release of ATP from urothelial cells was increased compared to controls. Contractions to ATP were reduced in obstructed urinary bladder of rats. There is P2X3R up-regulation in interstitial cells of Cajal in an experimental rat model of partial bladder outflow obstruction. In the pig, partial bladder outlet obstruction resulted in reduced contractions in response to electrical field stimulation as well as to purinergic agonists, but in the rat partial outlet obstruction model, contractions to ATP were increased after 2 weeks and 3 months. Patients with bladder outflow obstruction release higher amounts of ATP into the urine.
Botulinum Toxin A (BTXA) and ATP Release
BTXA is increasingly being used to treat detrusor overactivity. In an early paper, it was shown that BTXA inhibited ATP as well as ACh release from parasympathetic nerves. Recently, BTX has been shown to inhibit ATP release from the urothelium. Daytime frequency, urgency, nocturia and pain were decreased by injection of BTXA into the human bladder. BTX is used to treat OAB syndrome and bladder hypersensory states.
Chronic Alcohol Consumption and Bladder Function
Chronic consumption of ethanol impairs purinoceptor-mediated relaxation of detrusor smooth muscle of the rat. Ethanol also alters neuronal P2XR.
Diabetic Bladder
Damage to human urinary bladder autonomic nerves and disturbances in micturition in diabetes have been recognised for many years. Urothelial release of ATP has been reported to play a role in bladder dysfunction in type 2 diabetes. There is a transient increase in sensitivity of the STZ rat whole bladder preparation to α,β-meATP. The cholinergic component of nerve-mediated contractions was reduced in diabetic rat and rabbit bladders, but the purinergic component was increased.
In STZ mice, the urinary bladder had weaker nerve-mediated contractions in response to electrical field stimulation in contrast to normal mouse bladder. Ca2+ regulation of ATP release may be impaired in diabetes. Increased adenosine- and ATP-mediated relaxant responses, together with increased ATP-mediated contractile responses were observed in bladders from 8-week STZ diabetic rats. The enhanced contractions of STZ-diabetic rat bladders to nerve stimulation and ATP peaked between 6 and 9 weeks, but dropped to control levels by 12–20 weeks. There is also an increase in release of ATP in STZ female rat bladders. There is upregulation of P2X1R in the bladder of STZ-induced diabetes in the early phase, but downregulation of the P2X2R. Bladder overactivity occurring 2 months after induction of diabetes with STZ was accompanied by enhanced expression of P2Y2 and P2Y4R.
Bacterial Infection
Bacterial infection of the bladder causes urgency, urinary incontinence and overactivity. Urine ATP concentrations were reduced during episodes of bacteriuria. An ATP assay method has been employed for many years to test for bacteriuria in urine.
Bladder Cancer
The growth of bladder cancer cells is reduced by ATP, both in vivo and in vitro. Doxorubicin, used to treat bladder cancer, has side effects, such as increased urgency and urinary frequency. Quercetin, a plant-derived flavonoid, prevents bladder cancer in cells lines, by suppressing cell proliferation and inducing arrest of the cell cycle or cell death by inhibiting the activity of ecto-nucleotidases. In humans with bladder papillary carcinoma urothelial differentiation was correlated with the expression and localisation of P2X3 and P2X5R. High CD73 immunoreactivity was associated with reduced bladder tumour progression. P2X7R protein favoured survival of patients with bladder urothelial cell carcinoma.
Bladder Pain
In 1995, P2X3 homomultimer and P2X2/3 heteromultimer receptors were cloned and were localised on sensory nerve endings. Purinergic mechanosensory transduction was proposed, suggesting that release of ATP from urothelial cells as a result of distension stimulates P2X3 and P2X2/3R on suburothelial sensory nerve endings to activate high threshold nociceptive nerve fibres that reach the cortex pain centres. Distension of the bladder stimulates discharge in the nociceptive sensory nerves, which can be mimicked by ATP and can be inhibited by P2X3R antagonists. Stimulation of bladder P2X3R sensitises bladder afferent nerves, mimicking the sensitising effect of cyclophosphamide-induced cystitis. P2X3R are a potential target for therapeutic treatment of bladder pain. P2Y2R are also expressed on bladder sensory nerves and are claimed to mediate increased stimulation of P2XR-mediated activity, playing a role in bladder pain syndrome (IC).
Urethra
The principal non-adrenergic, non-cholinergic inhibitory transmitter to the urethra is NO, but a small component of purinergic neurotransmission is also involved. ATP causes urethral relaxation, probably via P2Y1R, in pigs, guinea-pigs, rabbits and hamsters. The responses to non-adrenergic, non-cholinergic nerve stimulation were blocked by α,β-meATP, indicating that the P2X1R subtype was involved.
Sensory nerve fibres supplying the urethra may release ATP during axon reflex activity. Prostaglandins, produced following stimulation of P2YR, contribute to contractions of the urethra in pathophysiological conditions. In the rat, SC19220 (a prostaglandin E1 antagonist), lowered detrusor tone leading to increased bladder capacity and decreased voiding efficiency. Some sensory functions in the urethra are mediated by afferent fibres that express P2X3R. A review that discusses the therapeutic opportunities offered by KATP channels in the urethra is available.
Ureter
The ureter motor innervation is sparse, perhaps because peristaltic activity is not neurogenic, but myogenic. The dominant nerves in the ureter are sensory, confined mainly to the suburothelial plexus. These nerves contribute to vesicoureteral reflux that activates reflexes that modulate urine delivery to the bladder.
ATP constricts the pig ureter, while intravesical adenosine evoked relaxation via A2BR. In the ureter, ATP, α,β-meATP and adenosine evoked transient decreases in the frequency of peristalsis. In the rat ureter expression of P2X1R was shown on smooth muscle, while P2X5 and perhaps P2X7R are expressed on urothelium and P2X6R in the layer beneath the urothelium. P2X3R are localised on subepithelial sensory nerves that mediate nociception produced by release of ATP following distension of urothelial cells. Some ureter purinoceptors are likely to participate in long-term (trophic) events during development and regeneration, such as cell proliferation, differentiation, migration and cell death. The human ureter releases ATP in response to distension and human ureteric suburothelial sensory nerves express P2X3R. In a review of the pharmacology and physiology of the human ureter, it was proposed that purinergic receptors may prove to be analgesic targets to treat ureteral colicky pain and to facilitate ureteral stone passage.
Seven days after unilateral ureteral obstruction of wild-type mice, it was shown that there was increased expression of P2X7R associated with fibrogenic responses and inflammation in the cortex. However, in P2X7R KO mice, the alterations seen in the wild-type mice were not present. It was suggested that P2X7R antagonists may play a role in preventing renal interstitial fibrosis. In A2AR KO mice with unilateral ureteral obstruction, there was a substantially increased progression of renal interstitial fibrosis.
Diseases of the Liver
In the liver, the two epithelial cell types that secrete bile, i.e., hepatocytes and cholangiocytes, express purinoceptor in the plasma membrane. Modulation of the release of ATP and purinergic signalling may be novel strategies to manage cholestasis and other bile flow disorders. Both quiescent and activated hepatic stellate cells (HSC) express purinergic receptors: P2Y2 and P2Y4R on quiescent and P2Y6R on activated HSC. P2YR on satellite cells could be a therapeutic target to treat or prevent liver fibrosis. Reviews concerned with purinergic signalling in liver disease are available.
Liver Injury, Inflammation, Immune Regulation and Repair
Purinergic signalling regulates the immune response in the liver. In A1R KO mice α-naphthylisothiocyanate-induced cholestatic liver injury was decreased. CD39-deficient mice treated with adenosine, probably via A2AR, were protected from reperfusion injury. A1R antagonists abolished ischaemic preconditioning. After the resection of bile-duct-ligated cirrhotic livers, an A2AR agonist improved liver function. Inhalation of high concentrations of hydrogen protects against ischaemia/reperfusion injury through A2AR activation. Adenosine, via A2B or A3R, accelerates the cell cycle during partial hepatectomy-induced liver regeneration in rats. In mice, ATL-146e, a selective A2AR agonist, prevented concanavalin A-induced acute liver injury.
P2Y2R activation in mice makes a major contribution to endotoxin-induced acute liver injury. In mice with acute liver injury, P2Y2R mediate neutrophil infiltration, regulating immune responses associated with death of hepatocytes. P2Y2R antagonists might be useful to treat inflammatory liver disease. A review discusses the role of purinergic signalling in sterile liver injury.
Infusion of ATP-MgCl2 was shown early to improve hepatic function and survival following hepatic ischaemia and after reperfusion. During ischaemia there is a substantial loss of ATP from hepatocytes. Resistance of hepatocytes to hypoxia is promoted by P2Y2R. In mice, CD39 deletion from natural killer (NK) cells reduced hepatic ischaemia/reperfusion injury, indicating that during liver regeneration ATP modulates NK cell function. UTP acting via P2Y2 and/or P2Y4R before induction of ischaemia attenuates post-ischaemic hepatocyte apoptosis resulting in a reduction of liver damage. Platelet aggregation triggered by ADP may have a role in ischaemia reperfusion injury.
ATP released from sympathetic nerves and from hepatocytes, may participate in the regulation of liver repair. In P2Y2R KO mice, hepatocellular proliferation is impaired, indicating that ATP has a trophic role in liver regeneration and growth after injury. ATP release following partial hepatectomy in rats regulates liver regeneration. Apyrase (CD39/NTPDase1) reduces extracellular ATP allowing NK cells to play a role in the regulation of the immune response and to improve liver regeneration. After partial hepatectomy, liver regeneration is enhanced by the KATP opener, diazoxide.
Hepatocyte lipoapoptosis contributes to hepatic inflammation in lipotoxic liver injury. Pannexin1 may contribute to hepatic inflammation by increasing ATP release in lipotoxic liver injury. Acetaminophen (APAP), used to reduce pain and fever, may damage hepatocytes. In mouse APAP-induced inflammation models, full injury following an overdose involved P2X7R activation. P2X7R activate hepatic caspase-1 as well as the migration of neutrophils into the liver, suggesting that ATP may play a major role in the development of inflammasomes following overdose of APAP. A438079, a P2X7R antagonist, is protective against APAP-induced liver injury. P2X4R are involved in liver regeneration after partial hepatectomy in mice. P2X1R-regulated IL-22 secretion is required for liver regeneration.
Fibrosis and Hepatic Stellate Cells (HSC)
Liver fibrosis followed by cirrhosis is a common cause of liver failure. HSC are the main fibrogenic cells of the liver, which express nucleotide receptors that are functional and mediate phospholipase D activity.
Adenosine A2BR play pro-fibrotic roles in human HSC. During fibrosis, HSC proliferate and undergo senescence and A2AR mediate both these key processes, suggesting that A2AR antagonists are potential antifibrotics. A2AR contribute to the pathogenesis of hepatic fibrosis and A2AR antagonists may reduce ethanol-induced stellate cell activation and fibrosis. MRS1754, an A2BR antagonist, reduced hepatic collagen deposition during fibrosis progression.
Activation of P2Y2 and P2Y6R regulates procollagen-1 transcription and may be targets to treat or prevent liver fibrosis, thereby avoiding cirrhosis and chronic liver failure. PPADS, a P2R antagonist, inhibited HSC proliferation and prevented the development of non-biliary liver fibrosis. NTPDase2 is a preferential ATPase that greatly influences inflammation and biliary type fibrogenesis. Ecto-5′-nucleotidase (CD73) gene expression in HSC and portal fibroblasts increased during myofibroblastic differentiation and is a therapeutic target for antifibrotic therapy.
Human platelet ATP release contributes to reduced type I collagen production and HSC activation in vitro. In progressive fibrosis, eicosapentaenoic acid replenishes hepatic levels of ATP leading to a reduction of steatosis and inflammation. Blockade of the P2X7R-NLRP3 inflammasome axis is considered to be a potential therapeutic target for liver fibrosis.
Cirrhosis
Liver injury induced by alcohol is associated with enhanced inflammatory responses and adenosine, acting via A2AR, may prove to be an effective strategy for reducing liver injury. During fulminant hepatitis, A2AR contribute to the anti-inflammatory actions that limit liver damage. In cirrhosis, platelet dysfunction is partly mediated by purinergic signalling. Cerebral A1R are involved in liver cirrhosis. Ectonucleotidase NTPDase 2 is down-regulated in biliary cirrhosis. It has also been claimed that endogenous A1R activation may protect mice against liver injury induced by acute ethanol by reducing oxidative stress and decreasing the accumulation of lipid. ATP-MgCl2 was used early to improve survival following massive hepatectomy in cirrhotic rats and adenosine partially reversed cirrhosis induced by carbon tetrachloride. In alcoholic liver disease, ATP and uric acid mediate inflammatory cross-talk between immune cells and hepatocytes. A2AR are involved in the pathogenesis of hepatic cirrhosis.
Hepatitis
In vitro infection by duck hepatitis B virus, Rous sarcoma virus, and hepatitis delta virus was inhibited by suramin. Sympathetic nerves influence immune-mediated experimental hepatitis and ATP released as a cotransmitter with NA is probably involved. In autoimmune hepatitis P2X7R regulate NKT cells. P2X7R activation participates in hepatitis delta and hepatitis B virus infection of human hepatocytes. Leptin-induced GLUT4 function in stellate cells in non-alcoholic steatohepatitis is mediated by P2X7R. Chronic hepatitis C virus infection evokes progressive liver disease, exhibiting cirrhosis, insulin resistance, fibrosis and finally liver cancer. P2X4 and P2X7R may be a major component of the purinergic signalling complex in hepatitis C virus-induced liver pathogenesis. In rats, A2AR stimulation inhibited hepatocyte lipotoxicity and non-alcoholic steatohepatitis. Adenosine, via A2AR, controls NKT-cell-dependent hepatitis induction. Purinergic mechanisms involved in autoimmune hepatitis have been reviewed.
Liver Transplantation
Human liver can be maintained successfully under hypothermic conditions for a maximum of 10 h using adenosine at high concentrations, although overcoming ischaemic damage is a major obstacle. However, infusion of ATP can preserve cells injured sublethally by enhancing their recovery following ischaemic injury and purinergic receptor antagonists prevent cold preservation-induced cell death. Upregulation of CD39 post-adenoviral infection prolongs transplant graft survival. After transplantation regeneration of the donor liver is important and ATP, via P2Y2R, activates hepatocyte cell cycle progression and proliferation in vitro and modulates growth factor activities in vivo. A2AR stimulation down regulated adhesion molecules, proinflammatory cytokines and ultimately improved liver function following liver transplantation in rats. In post-transplant allografts, purinergic signalling is used to predict as well as monitor progression of fibrosis and rejection. Blood from acute rejection patients showed raised intracellular levels of ATP in CD4+ lymphocytes.
Liver Cancer
Primary liver malignant tumours are subdivided in to hepatocarcinoma, bile duct carcinoma (cholangiocarcinoma) and hepatocholangiocarcinoma. ATP increases calcium uptake by rat hepatoma cells, probably via P2Y2 or P2Y4R subtypes. There is upregulation of P2Y2R in human hepatocellular carcinoma cells, which mediates proliferation and migration of the cells. Carcinoma-specific expression of P2Y11R make a major contribution to ATP-induced signalling that controls cell migration in human hepatocellular carcinoma cells. CD39 KO mice showed an increased incidence of spontaneous and induced hepatocellular carcinoma. Intra-arterial injection of an inhibitor of ATP production was suggested as a novel liver cancer therapy. The effects of ATP infusions in vivo on rat hepatocarcinomas have been investigated. P2X3R over-expression is involved in poor recurrence-free survival in hepatocellular carcinoma patients and identifies the P2X3R as a potential therapeutic target. Inhibition by adenosine of hepatoma cell growth was reported early.
The A3R agonist, CF101, inhibited liver metastasis (following colon carcinoma). CF102, another selective A3R agonist, has anti-inflammatory and anti-tumour effects on the liver and was studied in a clinical trial for hepatocellular carcinoma patients. A2BR are strongly expressed in human hepatoma cellular carcinoma. Mouse regulatory T cell CD39 expression mediated inhibition of NK cell activity and promoted hepatic metastatic tumour growth. Liver metastasis from colorectal cancer is one of the main causes of cancer-related morbidity and ATP-chemotherapy may effectively treat initially unresectable colorectal liver metastasis. In hepatocellular carcinoma, up-regulation of ATP-binding cassette transporter genes is mediated by cellular microRNAs.
Diseases of the Reproductive System
Reviews are available about purinergic signalling in the reproductive system in both health and disease.
Erectile Dysfunction
Abnormalities in purinergic signalling, including impaired ATP-mediated cavernosal relaxation, may contribute to erectile dysfunction associated with prostate enlargement and diabetes and may provide a target for therapy. Normal penile erectile function involves a fine balance between contraction and relaxation in the corpus cavernosum smooth muscle. The strong relaxation induced by ATP via P2YR on human corpus cavernosum is comparable to that produced by NO, thus ATP together with an NO donor may prove to be effective for erectile disorders. ATP released from sympathetic nerves leads to relaxation of cavernosum smooth muscle via P2Y4R, whereas ADP, after breakdown of ATP released from endothelial cells, acts via P2Y1R on endothelial cells to produce relaxation via NO. P2XR might also be involved.
In anaesthetised dogs, ATP and adenosine induce penile tumescence, probably via A2R; pelvic nerve stimulation also produced tumescence. Impaired adenosine signalling via A1R contributes to erectile dysfunction. Elevated adenosine signalling, via A2BR, may contribute to priapism, where there is persistent penile erection lasting at least 4 h without sexual excitation. A review highlights adenosine signalling in penile tissue as a potential therapeutic target to treat erectile disorders. Impaired erectile function occurs in CD73 KO mice resulting in decreased endogenous adenosine. Corpus cavernosum from men suffering from vasculogenic erectile dysfunction show lower ectonucleotidase CD39 activity resulting in ATP accumulation. Human corpus cavernosum relaxation by P2R agonists was substantially reduced in erectile dysfunction patients. ATP release from cavernosal tissue increased in patients following prostatectomy. Activating ATP-mediated pathways may restore erectile function in diabetics where there is impaired NO bioavailability. It has been suggested that P2X3 antagonists may improve recovery of erectile function.
Male Fertility and Contraception
ATP increases the fertilising potential of sperm in humans and is used to treat spermatozoa during in vitro fertilisation. In P2X1R KO mice fertility was diminished with decreased number of spermatozoa in the ejaculate. This raises the possibility that P2X1R antagonists would provide a safe and effective contraceptive. In rat testes, during spermatogenesis there is differential, stage-dependent immunostaining for P2XR subtypes, suggesting purinergic targets for both fertility and contraception. ATP triggers the acrosome reaction via P2X7R in human spermatozoa. Purinergic signalling plays a role in the maturation of sperm cells in the testes. When the selective P2X1 and P2X3R desensitiser, α,β-meATP, was injected into the cauda epididymis, fertility in male rats was impaired. Adenosine stimulates human sperm motility via A2R.
Prostatic Hyperplasia
Purinergic compounds have been suggested for the therapeutic treatment of benign prostatic hyperplasia. Injection of BTX into the prostate, which reduces ATP and ACh release, treats bladder obstruction hyperactivity, by decreasing prostate size and as such improving urine flow rate.
Disorders of the Female Reproductive Tract
Regulating the proliferation of ovarian granulosa cells as well as steroidogenesis contributes to ovarian pathophysiology, since in rats with polycystic ovarian syndrome, theca hyperplasia occurs. The hydrolysis of ADP and ATP was reduced by ovariectomy and oestradiol replacement therapy. Ovarian tumours arise largely from the surface of squamous-to-cuboid mesothelium covering the ovary. ATP stimulated mitogen-activated kinase in neoplastic and pre-neoplastic surface epithelium, suggesting that co-released ATP from sympathetic nerves may contribute to the regulation of cell proliferation in neoplastic epithelial cells from the surface of the ovary.
In the human fallopian tube, ATP-mediated contractions are increased during acute purulent inflammation, probably as a result of upregulation of P2X1 and P2X2R. It has been claimed that targeting P2X7R may lead to new treatments to prevent uterine contractions in preterm deliveries. A naturally occurring P2X7 splice variant, the P2X7jR, blocks P2X7R-mediated actions. It is co-expressed with P2X7R in female reproductive tract epithelia. The P2X7j isoform hetero-oligomerises with the P2X7R and co-expression of P2X7R and P2X7jR blocks ATP-induced pore formation, and abolishes agonist-induced apoptosis. P2Y2R agonists may be a non-hormonal alternative therapy for treating vaginal dryness in post-menopausal women. ATP is considered as a therapeutic target to control uterine activity during difficult labours.
The P2X7R contributes to the control of cervical infections. P2X7R-mediated activation of cervical epithelial cells inhibits Chlamydia and mycobacteria infection. ATP regresses endometriosis in a rat model. Adenosine in the placenta mediates the placental disturbances induced by alcohol, perhaps contributing to the pathogenesis of foetal alcohol syndrome. Adenosine protects vaginal epithelial cells from T. vaginalis cytotoxicity. Plasma adenosine is raised in hyperemesis gravidarum (severe morning sickness) and serves as a prejunctional modulator of sympathetic neurotransmission, which limits further progression of this pregnancy-related disease.
Preeclampsia
ATP infusion in pregnant rats involved an inflammatory response that occurs in preeclampsia. Elevated placental adenosine signalling contributes to the pathogenesis of preeclampsia. Hypoxia stimulates ATP release, which is rapidly broken down to adenosine by ectonucleotidases and women with preeclampsia and their foetuses have increased circulating adenosine concentrations. There is elevation of adenosine A2AR expression in placental biopsies, villous explants and placental microvillous membranes. In preeclampsia A2BR on microvascular endothelial cells have also been implicated. Reduced adenosine-mediated angiogenesis in preeclamptic pregnancies may be associated with hypertension development in the offspring. The interaction between A2AR and the angiotensin system may be involved in the early growth of the placenta. A2AR expression is raised in pre-eclampsia, perhaps as a consequence of poor placental perfusion in preeclampsia. Elevation of ADA activity in women with preeclampsia may contribute to their increased levels of uric acid and pro-inflammatory immune activity. Release of ATP increases in preeclampsia following hypoxia and oxidative/nitrative stress, which acts on P2X4R to influence homeostasis of the placenta. There is deficient spiral artery remodelling and trophoblast invasion in preeclampsia, both of which may be inhibited by ATP-induced activated macrophages. It was concluded from a study of the relationship between the foeto-placental adenosine release and utero-placental circulatory insufficiency in pregnancies featuring preeclampsia, that foetal plasma adenosine increases before utero-placental insufficiency induces generalised foetal hypoxia.
Prostate Cancer
Prostate cancer is the second most common male cancer and the third leading cause of cancer death. Prostate cancer cells are sensitive to extracellular ATP. ATP and adenosine inhibit the growth of human prostate cancer cells, identified at that time to act via P2Y1, P2Y2 and/or P2Y4, P2Y6 and P2Y11R subtypes. Activation of P2Y1R inhibited growth and induced cell death of prostate cancer PC-3 cells and P2Y1R agonists were claimed to be therapeutically promising for prostate cancer.
However, prostate tumour cells were shown later to also express P2X4, P2X5, and P2X7R in PC-3 cells and P2X4 and P2X5R in DU145 cells. ATP inhibited tumour cell growth, but not by UTP or adenosine, while 2′(3′)-O-(4-benzoylbenzoyl) ATP increased apoptotic cell death in PC-3 cells, probably via P2X7R. CD73 KO mice resist prostate carcinogenesis and CD73 promoted de novo prostate tumorigenesis. Anti-CD73 monoclonal antibodies decreased tumour growth and metastasis in the prostate.
There are many polymorphisms of the P2X7R, which, as well as resulting in loss of function, alter receptor activity. Cytolytic P2X7R expression was found in 116 prostate cancer pathology specimens. In normal tissues from patients with no evidence of cancer, P2X7R were not expressed, suggesting that the appearance of P2X7R is an early marker of prostate cancer.
Prostate tumour cell proliferation is inhibited by adenosine. A3R activation by IB-MECA inhibited proliferation of prostate cancer cells and induced cell cycle arrest and apoptosis. Activation of A3R suppressed prostate cancer metastasis. The ATP synthase β subunit also plays a role in prostate cancer metastasis.
Breast Cancer
Inhibition of growth of human breast cancer cells by ATP was shown for the first time in 1993. Chemotherapeutic ATP release from breast tumour cells of mice increased tumour regression through apoptosis and it was suggested that P2Y2 and/or P2Y4R were involved. Oestrogen, acting via oestrogen receptor α, promoted proliferation of breast cancer cells by down-regulating expression of P2Y2R and reducing P2Y2R-induced increase in [Ca2+]i. P2Y2R activation by ATP released from cancer cells induces the invasion of metastatic breast cancer cells. Up-regulation of P2Y6R occurs in the mesenchymal phenotype of breast cancer cells and inhibition of P2Y6R may be a useful therapeutic target for metastasis of breast cancer.
Antibody therapy with anti-CD73 inhibited breast tumour growth and metastasis. Bisphosphonates are also effective inhibitors of breast cancer. Proteomic analysis of human breast carcinoma revealed upregulation of ATP synthase in tumours and the ATP synthase inhibitor, aurovertin B, inhibited proliferation of several breast cancer cell lines. Malignant breast carcinoma cells release ATP making the pre-metastatic environment suitable for micro-metastasis in lymph nodes and associated afferent lymph vessels.
In breast tumour cells ATP increased [Ca2+]i and high concentrations produced apoptosis via P2X7R. Activation of P2X7R in the human breast cancer cell line, T47D, increased cell migration and development of metastases, suggesting that P2X7R antagonists may have therapeutic roles. The role of hypoxia in the regulation of tumour progression has been debated. However, P2X7R expression is increased by hypoxia and hypoxia-driven increase in P2X7R enhances tumour cell invasion and migration. Silencing of P2X5R inhibited cell proliferation and may be a new mechanism to target cancer metastasis.
A1 and A3R mRNA are expressed on human breast tumours. Adenosine induces tumour cell proliferation and migration of T-47D and MCF-7 breast carcinoma cell lines. MDA-MB-231, a human breast cancer cell line, expressed A2BR, which mediated cell proliferation and A2BR inhibition slowed growth of breast tumours. A3R agonists reduced bone metastasis of breast cancer, suggesting a therapeutic approach to bone-residing breast cancer.
Cervical Cancer
HeLa cells from human cervical cancer are used to study purinergic signalling involvement in cancer. Activation of P2Y2 R with UTP and ATP caused proliferation of HeLa cells. P2Y4 and P2Y6 R expression increased during proliferation. Stimulation of P2Y1R on HeLa cells triggered epidermal growth factor receptor mitogen signalling and P2Y1 antagonists reduced proliferation. Permeabilisation of cervical cancer cells to a cytotoxin is activated by P2YR. P2Y6R activation induces HeLa cell migration. Oestrogen reversed the apoptotic activity mediated by P2X7R in normal human cervix, but not in cervical epithelial cancer cells. A truncated P2X7R variant (P2X7-j), expressed in cervical cancer cells, antagonised the P2X7R through hetero-oligomerisation. Gentle mechanical stimulation released ATP from HeLa cells. The presence of ectonucleotidase in human cervical cancer cell regulates the levels of nucleotides, limiting their effects.
Ovarian Cancer
ATP raised [Ca2+]i and stimulated growth of SKOV-3 and OVCAR-3 human ovarian carcinoma cells. ATP may act as a messenger to control the ovarian epithelial cell cycle through P2Y2R on human ovarian cancer cells. A2R antagonists inhibited angiogenic activity of human ovarian cancer cells. The treatment of human ovarian carcinoma with cisplatin in the presence of ATP results in additive cytotoxicity. P2X7R were highly expressed in both human ovarian tumours and ovarian cancer cell lines and paracrine release of ATP acts on P2X7R to cause proliferation of ovarian cancer cells.
Uterine Cancer
P2Y2R play a role in the control of the cell cycle and in the suppression of proliferation of human endometrial carcinoma cells. The P2X7R has been used as a biomarker for uterine epithelial cancers. There is decreased P2X7R expression on endometrial epithelium in pre-cancerous and cancer cells. Activation of P2X7R-dependent apoptosis has a chemotherapeutic growth-preventive effect on pre-cancerous and early cancerous epithelial lesions. Loss of CD73 in endometrial cancer allows for tumour progression. A higher proportion of ADA2∗1/∗1 genotype was observed in women with uterine leiomyomas.
Skin Diseases
Reviews about purinergic signalling in the skin during health and disease have been published. Changes in P2R subtype expression occurs in the epidermis during proliferative disorders, such as psoriasis and scleroderma, and P2Y2R may be a novel target to treat these disorders. ATP plays an important role in wound healing, the defence response, innate immunity and inflammation in the skin and might be an important therapeutically in psoriasis and scleroderma.
Psoriasis
Psoriasis is a chronic skin disease involving epidermal hyperproliferation. ATP and parathyroid hormone-related protein increased proliferation in HaCaT cells and may account for the hyperproliferation that occurs in psoriasis. P2Y2R contribute to epidermal homeostasis and indicate a possible therapy for psoriasis. P2Y11R mediate IL-6 production in human keratinocytes, which is important in psoriasis. P2X7R signalling induces inflammation leading to differentiation of Th17 lymphocytes, which are involved in the pathogenesis and potential treatment of psoriasis. P2X7R play a role in shaping the inflammatory microenvironment in psoriasis. Strong P2X7R expression is confined to the basal layer cell membrane, while P2Y1R were expressed all through the psoriatic epidermis.
In the blood of psoriasis patients, there are high levels of adenosine. Adenosine raised cyclic AMP levels in lesions of epidermis from psoriasis patients. There is a defective purine nucleotide synthetic pathway in patients with psoriasis and nucleotide metabolism is altered in psoriatic keratinocytes. In psoriasis patients, ADA levels were significantly elevated in both serum and epidermis. It was concluded from a clinical trial that caffeine, a P1R antagonist, is an inexpensive, safe and effective treatment for psoriasis. The role of adenosine as an endogenous mediator of the pathogenesis of psoriasis has been reviewed and clinical trials for the use of A3R agonists for the treatment of psoriasis described. A2AR are upregulated in psoriasis and A2AR agonists may counteract inflammation in this disease. A2BR are also expressed by human epidermal keratinocytes and their expression is reduced in psoriasis.
Scleroderma
Scleroderma encompasses a spectrum of disorders that cause dermal fibrosis and systemic sclerosis (SSc). SSc is a severe disease of the connective tissue of affected organs, including the skin. Adenosine A2AR contribute to the pathogenesis of dermal fibrosis and may be a therapeutic target to treat and prevent dermal fibrosis in scleroderma. Fibroblasts from SSc patients had a high rate of spontaneous IL-6 release, which was increased by ATP stimulation. SSc fibroblasts expressed mRNA for P2X3, P2X4, P2X7, P2Y1, P2Y2, P2Y4, and P2Y6, suggesting a possible therapeutic role for P2R antagonists in SSc patients via modulation of fibroblast function.
Skin Inflammation
The skin is an immune defence organ. Chemical, immune-specific or physical insults evoke increased expression of proinflammatory mediators, in particular keratinocytes release chemokines. Release of ATP is associated with inflammation of the skin, as well as increase in expression of, in particular, P2X7 and perhaps P2Y1R, and subsequent release of proinflammatory cytokines. Skin inflammation is reduced by P2X7R antagonists.
In ectonucleotidase (CD39) KO mice, rapid ATP release from keratinocytes is triggered by irritant chemicals causing exacerbated skin inflammation. Ultraviolet (UV) radiation evokes ATP release from keratinocytes and P2Y6R mediate UV radiation-induced inflammatory responses. ATP, when released after trauma or infection, may enhance immunoresponses and P2R agonists may increase vaccine efficacy. A1 and A2R may function as cutaneous neurogenic pro-inflammatory mediators. Human skin keratinocytes infected by Staphylococcus aureus, which releases α-toxin, exhibited a transient reduction in cellular ATP levels. P2X3 and P2X2/3 nociceptive receptors on sensory nerve endings are increased in inflamed skin and antagonists to these receptors have been developed as analgesics.
Wound Healing
Topically applied A2B and particularly A2AR agonists promote cutaneous wound healing in both healthy and diabetic conditions. A2AR agonists also promote collagen production by dermal fibroblasts. Adenosine inhibits proliferation of vascular smooth muscle cells via A2R activation. A review discusses the involvement of A2A and A2BR signalling in wound healing and fibrosis.
ATP and ADP also play a role in wound healing. ATP, released by damaged cells and physiologically during gentle mechanical stimulation, contributes to wound healing, tissue repair and regeneration. Cutaneous wound healing is accelerated by Mg-ATP, probably by increasing synthesis of vascular endothelial growth factor. Release of ATP from platelets and other cells during wound healing results in an increase in [Ca2+]i in keratinocytes, associated with epidermal growth and differentiation. ATP improves ischaemic skin flap survival after surgery, while P2R antagonists accelerate barrier repair.
There is acute inflammation in the initial phase of wound healing. ATP is involved in the development of inflammation through P2X7R-mediated production and release of cytokines from immune cells. The presence of P2X7R on immune cells mediates killing of intracellular pathogens by stimulating apoptosis of the host macrophage, chemo-attraction and cell adhesion. In contrast, adenosine has anti-inflammatory effects. ATP released following infection and trauma acts as an endogenous adjuvant to increase the immune response and P2R agonists may enhance the efficacy of vaccines.
Wound healing also involves new vessel growth (angiogenesis) and both ATP and adenosine contribute to cell proliferation and migration during angiogenesis. In cultured porcine artery smooth muscle cells, ADP and ATP stimulate DNA synthesis and cell proliferation. ATP and UTP are mitogenic in human vascular smooth muscle cells and P2Y2 and P2Y4R might be involved.
Wound healing is delayed in denervated wounds. In a rat model of this, P2X5, P2X7, P2Y1, and P2Y2R expression was altered in the epidermis. P2Y1R expression was increased in the basal proliferating layer of keratinocytes in the regenerating epidermis, while P2Y2R were significantly decreased. ATP and UTP, probably via P2Y2R, increased proliferation of the MCS-P5 murine keratinocyte cell line, and enhanced wound healing in mice. ATP release and P2YR signalling mediate electric field-stimulated directional keratinocyte migration. A review discussed the clinical applications of purinergic compounds to enhance wound healing.
Warts
Warts are caused by human papillomavirus infection of epidermis basal keratinocytes. P2X5R staining was increased in warts. P2X7R immunoreactivity was found in hyperkeratotic areas of the stratum corneum and in nuclei of koilocytes in the wart suprabasal layers. The nuclei positive for P2X7R were shrunken, showing much more intense P2X7R staining. The expression of P2X7R in the nucleus of human papillomavirus-infected cells was associated with disruption of the cellular machinery. P2X7R agonists may be used to trigger apoptosis in these virally infected cells. P2X5 and P2X7R are being explored for the treatment of warts.
Allergy
Contact allergen sensitisation involves immune system activation by endogenous danger signals. P2X7R KO mice exhibit resistance to contact hypersensitivity. P2X7R KO dendritic cells do not induce sensitisation in response to contact allergens or release IL-1β in response to ATP. This suggests that P2X7R are crucial for release of ATP from skin in response to contact allergens. Interference with P2X7R signalling could be a therapeutic approach to prevent allergic contact dermatitis.
Hailey–Hailey and Darier Diseases
These are autosomal dominant skin disorders and are characterised by epidermal keratinocyte dissociation (acantholysis) at the epidermis suprabasal layer. In lesions P2Y2R are not localised on acantholytic cells, but P2X7R appear in the plasma membranes, potentially mediating apoptosis.
Barrier Function
The skin protects the water-rich internal organs from environmental dryness, with the stratum corneum being critical to the water-impermeable barrier. Topical application of ATP and α,β-meATP via P2XR delayed barrier recovery, damaged by surfactant, organic solvent or tape stripping. P2R antagonists, however, accelerated barrier repair. In mice skin wounds healed faster following treatment with ATP-encapsulated fusogenic lipid vesicles rather than with lipid vesicles. PPADS, a P2XR antagonist, accelerates skin barrier repair and prevented epidermal hyperplasia.
Burns
There is increased concentration of adenosine in burn blister fluid, and depletion of ATP in skin after thermal injury. ATP has a protective effect against skin burns. ATP-MgCl2 administration following burn injury reversed the damage to the intravascular clearing of lipid emulsions within the reticuloendothelial immune system. Glucose metabolism was affected by ATP in thermally injured skin.
Burn injury produces severe pain and the relieving effects of tetramethylpyrazine, a Chinese medicine, are claimed to be due to it acting as a P2X3R antagonist. Skin P2X3R expression was increased on sensory nerve terminals in first and second degree burns, but, following treatment with tetramethylpyrazine, P2X3R expression was reduced. P2X3R may play a role in the short-lasting thermal hyperalgesia induced by mild heat injury. After a superficial skin burn, adenosine reduced the skin area showing hypersensitivity.
Pain
Skin pain is associated with changes in sympathetic nerve activity and ATP released from rat sympathetic nerves as a cotransmitter with NA may modulate cutaneous nociceptors. P2X3R are expressed on sensory neurons in DRG, nodose and trigeminal ganglia that innervate cutaneous tissues. ATP and ADP stimulate skin afferent nerve terminals and skin cell damage stimulates nociceptive sensory nerves via ATP release. In rat skin with carrageenan-induced inflammation, nociceptors can be selectively activated with α,β-meATP, indicating the involvement of P2X3R. ATP contributes to the enhanced sensitivity of inflamed skin nociceptors, leading to heat hyperalgesia. P2X3R antagonists are anti-nociceptive. UV light evokes hypersensitivity of skin to ATP-induced pain. After subcutaneous bee venom injection, there is reduction of prolonged pain by PPADS, and it was suggested that stimulation of P2XR in the spinal cord contributes to cutaneous pain. The terminals of nociceptive neurons in the skin are targets for P2X3R antagonists. UTP sensitises a subpopulation of cutaneous C-fibre nociceptors to mechanical stimuli. There is increased P2X3R expression on calcitonin gene-related peptide-positive sensory fibres during the growth of tumours, mediating nociception. Increased expression of skin glial cell neurotrophic factor increases the mechanical sensitivity of nociceptive afferents expressing P2X3R.
Ecto-5′-nucleotidase (CD73) is located on nociceptive terminals and epidermal keratinocytes in the epidermis, which, by hydrolysing AMP to adenosine, is suggested to be anti-nociceptive. Blockade of peripheral P2Y1R prevents thermal hyperalgesia. Mechanical allodynia is induced by α,β-meATP, which sensitises P2X3R on cutaneous nociceptive sensory fibres.
Reviews with coverage of purinergic signalling and cutaneous pain are available.
Dermatitis
In irritant dermatitis, there is a pathogenic role for keratinocyte-derived ATP. The necrosis produced by the chemical irritant croton oil was prevented by the pre-treatment with A438079, a selective P2X7R antagonist. Topical application of A2A antagonists prevents radiation dermatitis.
Skin Cancer
Different subtypes of P1R and P2R are involved in skin cancer, playing roles in differentiation, apoptosis and proliferation. The roles of purinoceptors are complicated because there are multiple receptor subtypes on the same cell, which can have opposing effects. For example, P2Y2R mediate an increase in tumour cell numbers, while P2Y1, P2X5, and P2X7R mediate a decrease in cell numbers. In cancers of the skin, proliferation outweighs apoptotic cell death.
UV light is a stimulus for the genesis of cutaneous cancer, including basal and squamous cell carcinoma as well as melanoma, where the UV-B component has the most severe effects. UV-B irradiation decreases the amount of P2X1, P2Y2, and P2X7R, which contributes to the malignant transformation of keratinocytes.
Basal and Squamous Cell Carcinomas
Basal cell and squamous cell carcinoma are tumours that generally occur after the age of 50, squamous cell carcinoma being the more common and aggressive of the two. Nucleoside analogues reduced basal cell carcinoma growth. A human cutaneous squamous cell (epidermal) carcinoma cell line, A431, express P2R that induce increases in [Ca2+]i. ATP-stimulated A431 cells induced production of inositol-trisphosphate, suggesting the involvement of P2YR. P2X5 and P2YR were strongly expressed on both squamous and basal cell carcinomas. P2X7R are expressed in apoptotic cells in superficial multifocal and infiltrative cells and in the necrotic centre of nodular basal cell carcinomas. Expression of P2Y1R was confined to the stroma surrounding tumours. P2Y4R were present only in basal cell carcinomas. ATP and UTP at low concentrations induced an increase in the number of A431 cells, while high concentrations substantially decreased cell numbers.
ATP via P2X7R caused apoptosis of A431 cells and UTP and adenosine (after ATP breakdown) also induced cell death. 2′(3′)-O-(4-Benzoylbenzoyl) ATP, a potent P2X7R agonist, reduced skin carcinoma and papilloma and formation. ADA in saliva was shown to be a diagnostic marker of tongue squamous cell carcinoma.
Melanoma
Malignant melanoma, which is highly metastatic, is derived from melanocytes. ATP inhibited the growth of both human and animal melanoma cells in vivo. CD39 is over-expressed in differentiated human melanomas. Expression of P2X7R was increased in superficial spreading melanoma patients, which were later shown to be functional and may be a therapeutic target for melanoma therapy. A low pH environment as seen in solid tumours induced ATP release from B16 melanoma cells, which increases proliferation via P2X7R. Oxidised ATP, a P2X7R antagonist, inhibited tumour growth. P2Y1, P2Y2, and P2Y6R mRNA and protein expression was observed in human melanomas. The presence of P2Y1 and P2X7R, which had been suggested to be therapeutic targets for melanoma treatment using ATP, was demonstrated by immunohistochemistry. The release of ATP from murine B16 melanoma cells was shown to upregulate CD39 expression on regulatory T cells. Dying tumour cells release ATP, which accumulates at high concentrations and acts as an immune danger signal, although it can also kill adjacent tumour cells directly via P2X7R. Accelerated melanoma tumour progression in mice lacking P2X7R has been reported. γ-Irradiation that induces arrest in tumour cell growth and death, induced P2X7R-dependent release of ATP from B16 cells.
In an animal model of melanoma, tumour growth was reduced in CD73 KO mice. Implanting B16 cells into CD73 KO mice, thereby decreasing the production of adenosine, resulted in reduced tumour growth. Adenosine potentiated the in vivo actions of chemotherapeutic agents. Antimetastatic therapies based on inhibition of A1R activation have been suggested. A1, A2A, A2B and A3R subtypes are expressed in the A375 human malignant melanoma cell line. A3R activation resulted in growth inhibition of melanoma cells. However, another study claimed that adenosine, acting through A3R, induced cell proliferation of human malignant melanoma C32 cells. A2BR antagonists impaired IL-8 production that is raised in malignant melanoma patients, while A3R antagonists decreased vascular endothelial growth factor that promotes human carcinoma cell angiogenesis and metastasis. Adenosine is a potent immunoregulatory factor modulating cytotoxic activity and cytokine production of anti-melanoma specific T cells.
In conclusion, P2Y2R mediate proliferation, P2X5R mediate differentiation (i.e., are antiproliferative) and P2X7R mediate cell death. Therefore, P2Y2R antagonists and P2X5 and P2X7R agonists have therapeutic potential for the treatment of skin cancer.
Musculoskeletal Diseases
Reviews that include discussion of the pathophysiology of musculoskeletal diseases have been published. There are multiple purinoceptor subtypes expressed by bone and cartilage, which are potential targets for original therapeutic strategies to inhibit bone resorption in osteoporosis, rheumatoid arthritis (RA), periodontitis and tumour-induced osteolysis.
Muscular Dystrophy
ATP was used early to treat myopathies, although the mechanism of action was not known. Allopurinol has been used for the treatment of Duchenne muscular dystrophy (DMD). It counteracts low purine nucleotide degradation levels that occur in Duchenne muscle, but chronic administration of allopurinol failed to improve DMD symptoms. Lymphoblastoid cells from DMD patients were found to be highly sensitive to ATP stimulation.
The mdx model of DMD, lacking the dystrophin protein, mimics muscle damage and subsequent regeneration. Sequential expression of P2X5, P2Y1 and P2X2R was described during muscle regeneration in the mdx model. It was claimed recently that a P2Y2R antagonist may ameliorate cardiomyopathy in DMD. P2Y1R were expressed on infiltrating immune cells. A purinergic dystrophic phenotype was seen during the earliest stage of developing dystrophic muscle. Dystrophic myoblasts express P2X4 and P2X7R proteins and it was claimed that antagonists to these receptors may be of potential therapeutic benefit. ATP signalling is altered in muscular dystrophy, but was partly recovered after nifedipine treatment. It was claimed that dihydropyridines may be used as a therapeutical tool to reduce muscle damage observed in dystrophic muscles. It was suggested that P2XR antagonists alter the adaptive immune component in the muscle infiltrates in DMD and are a promising therapeutic approach to treat DMD.
Myofascial pain is a feature of DMD and ATP stimulates myofascial nociceptors. P2X7R upregulation occurs in dystrophic mdx mouse muscles and treatment with P2X7R antagonists slows the progression of DMD. Sensitivity to ATP is higher, release of ATP is greater and expression of P2Y2R is increased, but P2Y1R expression is decreased in mdx mice. A review about purinergic receptors in DMD was published.
Myasthenia Gravis (MG)
Myasthenia gravis is an autoimmune disease, which affects the neuromuscular junction. Lack of neuronal A2AR-mediated Cav 1 (L-type) influx causes tetanic failure in MG. It was suggested that the adenosinergic pathway was dysfunctional in autoimmune MG and that stimulation of CD73 activity and A2AR may have therapeutic potential for MG.
Fibromyalgia
Fibromyalgia (a musculoskeletal disease) is characterised by allodynia, as well as mood disorders. In fibromyalgia patients, there are decreased levels of ATP in platelets perhaps contributing to the pathogenesis of the disease.
Osteoporosis
Osteoporosis, characterised by bone mass loss (bone mineral density decrease), leads to a high risk of bone fracture. The P2X7R is considered to be important in relation to the treatment of osteoporosis. P2X7R plays a critical role in both cortical and cancellous bone mass augmentation and were shown to stimulate cancellous and periosteal bone formation and inhibit cancellous bone resorption during growth. Single nucleotide polymorphisms of the P2X7R gene are associated with the risk of fractures, decrease in bone mineral density and osteoporosis. P2X7R are involved in the formation of human osteoclasts. P2X7R antagonists are being considered for the treatment of osteoporosis and with remodelling disorders, where bone mass is reduced. Skeletal pain accompanies osteoporosis and P2X2/3R might have a role in osteoporosis patients under a high bone turnover state. P2X5R may be a therapeutic target for treatment for inflammatory bone loss. Polymorphisms in the P2X4 and P2X7R genes and the Leu46Pro polymorphism of the human P2Y2R gene were linked to bone mineral density and the risk of osteoporosis in Dutch fracture patients. It was suggested that clopidogrel, a P2Y12R antagonist used for stroke and thrombosis, increases the risk of fractures in osteoporotic patients. P2Y13R antagonists have also been proposed for the treatment of osteoporosis.
Adenosine receptors are involved in osteoporosis. Trans-differentiation of osteoblasts to adipocytes, which involves A2BR, may contribute to the pathogenesis of osteoporosis. P1R might be targets for treating osteoporosis and other diseases characterised by excessive bone turnover.
Osteoarthritis (OA)
Osteoarthritis is a degenerative joint disease as a result of wear of the articular cartilage due to abnormal load to the joint or from infection, trauma or due to ageing. The pain from OA is due largely to inflammation. Increased ATP levels and 5′-nucleotidase activity are present in osteoarthritic joint synovial fluid, compared to the joints from RA patients, particularly from osteoarthritic patients where deposition of calcium-containing crystals were also present. ATP contributes to pathologic mineralisation in articular cartilage and therefore P2R antagonists might provide therapeutic tools for crystal-associated arthritis. ATP levels in knee synovial fluid of patients with OA are related to pain intensity. P2X3 and P2X2/3R play an important role in the development of articular hyperalgesia of arthritic joints. In the long-term complications following total hip arthroplasty, different polymorphic variants of the P2X7R are associated with high or reduced periprosthetic osteolysis. There are elevated concentrations of ATP in the synovial fluid of dogs with OA. Purinergic signalling, via P2R, produces calcium oscillations in migratory chondrogenic progenitor cells isolated from OA cartilage. Platelets promote cartilage repair and chondrocyte proliferation via release of ADP in a rodent model of OA, suggesting that P2Y1 or P2Y12R agonists may be useful for treatment of OA. Treatment with the selective P2X7R antagonist, AZD9056, produced pain-relieving and anti-inflammatory effects in rats with OA.
Adenosine signalling is also involved in OA. Adenosine, produced following breakdown of ATP, is released from chondrocytes and contributes to tissue damage in arthritic conditions. The regulation of LPS-induced IL-6 release involves A2AR, indicating that adenosine has a regulatory role in controlling osteoclastogenesis and inflammation. Electromagnetic field stimulation up-regulates A2AR in synovial fibroblasts and adenosine, acting through both A1 and A2AR, had anti-inflammatory activity to control joint inflammation. A2A and A3R agonists modulate prostaglandin E2 and cytokine release in human osteoarthritic fibroblasts. Adenosine receptors also mediate regulation of inflammatory responses in human synoviocytes. A2AR agonists are used to reduce joint destruction due to septic arthritis. A2AR deletion resulted in the development of OA in mice, suggesting that A2AR agonists might be a target for the treatment of OA.
Rheumatoid Arthritis (RA)
The potential involvement in RA of purinergic signalling was recognised first in the 1990’s when concentrations of adenosine, after released ATP was broken down, were reduced in synovial fluid in RA compared to OA. Increased levels of adenosine as a treatment for RA was suggested. UTP and ATP activate calcium-mobilising P2UR to synergistically act with IL-1 to stimulate release of prostaglandin E2 from human rheumatoid synovial cells. Hypotonic stress promotes ATP release and cell proliferation via transient receptor potential vanilloid 4 activation in RA rat synovial fibroblasts.
IL-1β is a proinflammatory cytokine that substantially contributes to the progression of RA. ATP, through P2X7R, induced increased levels of IL-1β in RA patient blood samples compared to control samples. Mononuclear cells from these patients were more sensitive to stimulation by ATP, possibly because of P2X7R genetic polymorphism. P2X7R are involved in the pathogenesis of RA and systemic lupus erythematosus. P2X7R mRNA and protein are expressed in human rheumatoid synoviocytes. Studies of arthritis animal models suggest an in vivo role for the P2X7R in the progression of this inflammatory disease. There was a lower incidence and reduced severity of the symptoms of arthritis induced by anti-collagen treatment in P2X7R KO mice. Therefore targeting the P2X7R may be a potential treatment for RA. P2X7R antagonists in the collagen-induced animal model of RA reduced destruction of peripheral inflammatory tissue. In a later study, it was claimed that AZD9056, a P2X7R antagonist, was not effective against RA. P2X7R antagonists are being investigated for clinical use against inflammatory joint pain. A multicentre, double-blind, placebo-controlled clinical trial showed that ATP infusions reduced inflammation and disease symptoms in patients with RA.
Bovine chondrocytes express P2X1 and P2X3R and following stimulation there was release of inflammatory mediators. Therefore antagonists to these receptors may be therapeutically useful for articular cartilage resorption and diseases involving inflammation. There was an increased platelet response to ADP in RA patients.
Sympathetic nerves mediate proinflammatory responses during the initial phase of arthritis induced by type II collagen, probably via cytokines such as interferon-γ released in response to the sympathetic cotransmitters ATP and NA. α,β-MeATP-sensitive P2XR (probably P2X3) are expressed on rat knee joint peripheral nociceptive afferent fibres and the increased ATP levels in damaged and inflamed tissues, may contribute to nociception and pain. P2X3R were found on nociceptive sensory fibres in lumber facet joints, where low back pain originates. Changes in P2X3R expression on DRG neurons that label isolectin B4 were seen following the induction of RA. P2X3R expressed on trigeminal ganglia also contribute to orofacial pressure pain in monoarthritis of the temporomandibular joint. Plasma extravasation in the rat knee joint induced by bradykinin was enhanced by ATP, released as a cotransmitter from sympathetic nerves. Intravenous guanethidine, which inhibits release of sympathetic cotransmitters, proved to be effective in RA patients. Uncaria tomentosa extract affects the metabolism of adenine nucleotides and has been suggested as an adjuvant to treat arthritis.
The evidence showing a role for adenosine in RA has been reviewed. Increased activity of ADA was seen in synovial fluid from patients with RA as well as in rheumatoid synovial fibroblasts. The ImmuKnow assay might effectively identify RA patients that are more at risk of developing infections. Signalling via the A2AR caused modification of the cytokine milieu in RA. Over-expression of A3R was observed in peripheral blood mononuclear cells of RA patients. Patients with RA had greater expression A3R in the synovium. There are increased levels of A2A and A3R on the lymphocytes and neutrophils of RA patients. In the dorsal horn of rats with induced RA, A1R agonists decreased activation of c-fos and astrocytes. In a later study of the adjuvant-induced monoarthritis model an A3 specific agonist prevented bone resorption. ATP, working via A2R, also reduced joint injury. A phase II clinical trial provided evidence for A3R agonists as a treatment for RA. CGS 21680, an agonist of the A2AR, reduced progression of murine type II collagen-induced arthritis. A2AR agonists ameliorate adjuvant-induced arthritis in rats. Methotrexate (MTX) is often used to treat RA. In human joints with inflammatory disease, MTX treatment involved A2AR. Adenosine via A2BR prevented MTX-induced inhibition of osteoclast bone destruction in arthritis induced by adjuvant. In RA patients treated with MTX, studies of polymorphisms of the genes involved in adenosine release concluded that genotyping may help identify patients who would most benefit from MTX treatment. Anti-tumour necrosis factor-α has also been used to treat RA, but it raises the risk of reactivating tuberculosis. ADA assay is a specific and sensitive test for the quick diagnosis of rheumatoid effusions.
Tooth Pain
There are many sensory nerves, originating in the trigeminal ganglia, expressing P2X3R in tooth pulp and ATP is released from odontoblasts in response to mechanical stimulation to act on these receptors, resulting in pain. LPS-induced pulp inflammation increased the expression of P2XR in trigeminal sensory nerves. Mechanical or cold stimulation of odontoblast processes in dentin tubules, results in ATP release and dental pain. Therefore P2X3R antagonists may be therapeutically useful to reduce toothache.
Bone Cancer Pain
Bone metastases, common in prostate and breast cancer patients, may cause substantial bone loss and pain. Purinergic signalling involvement in bone cancer was initially reported in the 1990’s when P2U (i.e., P2Y2/P2Y4) receptors were cloned from osteoclastoma. The expression of P2Y2R from human osteoclasts from bone giant cell tumour was later reported. Butyl benzyl phthalate, which interferes with mammalian ion channel receptors, inhibited ATP-induced cell proliferation via P2XR in human osteosarcoma HOS cells. ATP was used in autologous bone marrow transplantation for removing residual tumour cells. In mice, a type of human apyrase, APT102, in addition to aspirin disrupts bone metastasis. Release of ATP from tumour cells further stimulates osteoclast formation and activity, contributing to bone destruction that often happens around tumour metastases. Bisphosphonates, used to treat osteoporosis, treat bone cancer and may involve apoptosis induced by ApppI, an ATP analogue produced by bisphosphonates.
Purinergic signalling plays a role in bone cancer pain. Bone pain can be relieved by radiation therapy, which may be related to the Ca2+-signalling cascade, mediated by P2X6R. In a mouse model of cancer pain, increased expression of P2X3R on calcitonin gene-related peptide immunoreactive DRG neurons during tumour growth, it was claimed that ATP had a role in cancer-related pain. In rats, systemic inhibition of P2X3 and P2X2/3R with AF-353 strongly attenuated bone cancer pain-related behaviour. In mice, administration of A-317491, a selective P2X3 and P2X2/3R antagonist, attenuated the early stages of bone pain in cancer. Functional up-regulation of P2X3R has been described in DRG of bone cancer pain in a rat model.
In P2X7R KO mice, bone cancer pain-related behaviours had an earlier onset. Most human osteosarcomas expressed P2X7R isoforms A and B and P2X7R are involved in cancer-induced bone pain and P2X7R antagonists were suggested as a useful analgesic target. P2Y1R signalling in the DRG and spinal cord may mediate pain from bone cancer. Activation of KATP channels at the spinal cord level reduces pain associated with bone cancer. Stimulation by AMP-activated protein kinase suppresses neuroinflammation and reduces bone cancer pain.
Myeloma
Multiple myeloma (cancer of plasma cells) involves osteolytic bone lesions, due largely to enhanced osteoclast activity. A2R may be therapeutically useful to treat and prevent multiple myeloma-induced bone disease as activation of A2AR reduces osteoclast function, while activation of A2BR stimulates osteoblast differentiation. 8-Amino-adenosine is another possible therapeutic compound for the treatment of multiple myeloma.
Severe Combined Immunodeficiency
A major cause of severe combined immunodeficiency are genetic defects in the ADA gene. Lack of ADA causes accumulation of adenosine. Bone defects as a result of reduced osteoclastogenesis together with a defect in osteoblast function leading to low bone formation were seen in about a half of early-onset ADA-deficient patients. Further, the microenvironment of bone marrow in ADA KO mice had a lower ability to support haematopoiesis. In ADA KO mice, treatment with gene therapy, bone marrow transplantation or enzyme replacement, led to a full recovery. ADA-transduced hematopoietic stem cell gene therapy also enhanced the growth of children with this disease.
Dwarfism (Achondroplasia)
This is a congenital dysplasia of the skeleton as a result in a mutation in the gene encoding fibroblast growth factor receptor type 3 (FGR3). Ap4A diminished the expression of the achondroplasic FGFR3 receptor and P2Y1, P2Y2, P2Y6, and P2Y11R are expressed by achondroplasic chondrocytes mediating the action of Ap4A. Ap4A reversed the morphological changes supporting a therapeutic role for Ap4A as a possible treatment of dwarfism.
Paget’s Disease
There is an increase in osteoclast numbers in Paget’s disease, leading to an increase in bone resorption and a high turnover of bone. Bisphosphonates have been employed as a treatment for Paget’s disease and P2X7 antagonists have also been considered.
Ossification of the Posterior Longitudinal Ligament of the Spine
This disease causes neurological damage as a result of ectopic bone formation in spinal ligaments. In this disease, extracellular ATP in ossification of cell cultures of the posterior longitudinal ligament of the spine (OPLL) is increased. P2Y1R are highly expressed in OPLL cells. Mechanical stress and ATP increase the levels of osteopontin and alkaline phosphatase mRNA in OPLL cells, effects that can be inhibited by MRS2179, a selective P2Y1R antagonist. Over-expression of P2Y1R in OPLL-induced mineralisation resulted in ectopic bone formation in the spinal ligament cells of patients with OPLL.
Concluding Comments
Clinical interventions involving purinergic signalling are just beginning. However, the beginning and future of purinergic compounds for the treatment of a wide range of diseases is described in this review. P2Y12R antagonists, such as clopidogrel and ticagrelor, are currently in wide use for stroke and thrombosis, as are P2Y2R agonists for dry eye and A1R agonists for supraventricular tachycardia. The use of P2X7R antagonists for the treatment of inflammatory diseases is promising, but the presence of polymorphic variations of this receptor is holding up the development of selective antagonists appropriate for each disease. P2X3R antagonists are in clinical trials for use against visceral pain, chronic cough and hypertension. A2AR agonists are in use for the treatment of PD, and perhaps soon in wider use. P2X1R antagonists are being investigated for treatment of bladder disorders and hypertension, while P2X4, P2X7 and A3R antagonists are being explored for neuropathic pain. Treatments with inhalation of ectonucleotidases to alter the balance of ATP and adenosine and inhibitors of ATP release, are also a therapeutic approach being explored. The development of novel purinergic compounds by medicinal chemists that are orally available and stable in vivo would be a significant advantage in developing therapeutic approaches, including centrally penetrant P2X7R antagonists.
The majority of the therapeutic approaches for many heart disorders based on purinergic signalling manipulation are not fully understood yet and strategies to overcome the side-effects of treatment need to be considered. The pathophysiological roles of purinergic signalling in blood vessels are clearer and it plays an important role in controlling vascular tone and remodelling. Immunologic factors related to purinergic signalling are attracting more attention and should be considered. Human embryonic stem cells are able to self-renew and have the potential to differentiate into different cell types, including cardiovascular progenitor cells. This system of differentiation is being investigated for cardiac regenerative therapy. The single nucleotide polymorphisms in purinergic receptor genes and their association with diseases are being explored for potential use as diagnosis biomarkers (see ). Purinoceptors modulate neural stem cell proliferation, differentiation, migration and cell death and could be therapeutic approaches for the treatment of neurological and psychiatric illnesses. MicroRNAs modulating purinergic signalling are gaining interest as potential original therapeutic targets and disease biomarkers.
Although still in its infancy, clinical use of purinergic compounds has started. Several relevant pharmacological interventions are currently in clinical use. The lack of more established purinergic therapies may be due to there being relatively few receptor subtype-specific agonists and antagonists that are both effective and stable in vivo (see ). In some situations, a degree of redundancy is present, with several different subtypes of receptor mediating similar functional effects. Purinergic signalling is implicated in multiple disorders and therefore offers many potential future therapeutic targets. It should be noted, however, that since most purinoceptors are ubiquitous, to selectively target specific cell types may prove to be a challenge. As well as the development of selective agonists and antagonists, therapeutic strategies will probably include compounds that control P2R expression, inhibitors of extracellular ATP breakdown and inhibitors or enhancers of ATP transport. Understanding the interactions of purinergic signalling with other established signalling systems will be necessary.
Author Contributions
The author confirms being the sole contributor of this work and approved it for publication.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SS and handling Editor declared their shared affiliation.
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Gu B. J. Field J. Dutertre S. Ou A. Kilpatrick T. J. Lechner-Scott J. (2015 ). A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis. Hum. Mol. Genet. 24 5644–5654.
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Hansen R. R. Nielsen C. K. Nasser A. Thomsen S. I. Eghorn L. F. Pham Y. (2011 ). P2X7 receptor-deficient mice are susceptible to bone cancer pain. Pain 152 1766–1776.
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Hofman P. Cherfils-Vicini J. Bazin M. Ilie M. Juhel T. Hébuterne X. (2015 ). Genetic and pharmacological inactivation of the purinergic P2RX7 receptor dampens inflammation but increases tumor incidence in a mouse model of colitis-associated cancer. Cancer Res. 75 835–845.
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Hu F. Hui Z. Wei W. Yang J. Chen Z. Guo B. (2017 ). Hypotonic stress promotes ATP release, reactive oxygen species production and cell proliferation via TRPV4 activation in rheumatoid arthritis rat synovial fibroblasts. Biochem. Biophys. Res. Commun. 486 108–115.
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Hu H. Yang B. Li Y. Zhang S. Li Z. (2016 ). Blocking of the P2X7 receptor inhibits the activation of the MMP-13 and NF-κB pathways in the cartilage tissue of rats with osteoarthritis. Int. J. Mol. Med. 38 1922–1932.
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Hu X. Liou A. K. Leak R. K. Xu M. An C. Suenaga J. (2014 ). Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles. Prog. Neurobiol. 11 60–84.
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Hupertan V. Neuzillet Y. Stücker O. Pons C. Leammel E. Lebret T. (2012 ). Effects of nucleotides adenosine monophosphate and adenosine triphosphate in combination with L-arginine on male rabbit corpus cavernosum tissue. Int. J. Androl. 35 860–866.
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Jin H. Seo J. Eun S. Y. Joo Y. N. Park S. W. Lee J. H. (2014 ). P2Y2R activation by nucleotides promotes skin wound-healing process. Exp. Dermatol. 23 480–485.
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Kawai Y. Kaidoh M. Ohhashi T. (2008 ). MDA-MB-231 produces ATP-mediated ICAM-1-dependent facilitation of the attachment of carcinoma cells to human lymphatic endothelial cells. Am. J. Physiol. Cell Physiol. 295 C1123–C1132.
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Khalid M. Brisson L. Tariq M. Hao Y. Guibon R. Fromont G. (2017 ). Carcinoma-specific expression of P2Y11 receptor and its contribution in ATP-induced purinergic signalling and cell migration in human hepatocellular carcinoma cells. Oncotarget 8 37278–37290.
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