Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 22, 2026.

Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies

Mingyi Zhao, Ping Zhu, Masayuki Fujino and 5 more

International Journal of Molecular Sciences · 2016 · Review · CC BY

doi:10.3390/ijms17122078

Abstract

Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Hypoxic-ischemic encephalopathy (HIE), which is induced by the disruption of cerebral blood flow and a subsequent lack of oxygen to the affected area, is one of the leading causes of increased risk of death and lifelong disability, such as visual impairment, learning impairment, epilepsy, mental retardation, blindness, and cerebral palsy. The prevention and treatment of this disease remains a severe medical issue with global financial repercussions. One of the most widely accepted pathophysiological mechanisms of HIE involves the generation of oxidative stress.

Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Following the hypoxic-ischemic event, oxidative stress, which later triggers the release of oxygen and nitrogen species, calcium overloading, free radical generation, excitotoxicity, acidotoxicity, ionic imbalance, inflammation, apoptosis, autophagy, and necrosis, plays an important role in pathogenesis.

Strong evidence indicates that when the delicate balance between pro-oxidants and antioxidants tips toward a more oxidative state, local reactive oxygen species (ROS) production is dramatically increased. If available in appropriate amounts, ROS have been shown to act as signal transduction molecules providing cell protection and maintain in homeostasis. In contrast, when exceeding the buffering capacity of scavenging molecules and antioxidant enzymes, ROS are shown to cause significant damage to biological macromolecules, such as proteins (membrane protein degeneration), lipids (lipid oxidation), and nucleic acids (DNA degeneration). These derivatives induce a complex interplay of multiple pathways including immune defense, cell signaling, and induction of mitogenesis. In this review, we highlight the molecular mechanism for oxidative stress in HIE and examine potentially powerful clinical therapeutic strategies.

2. Overview for ROS Formation, Decomposition, and Sources

The main formation and decomposition of ROS has been shown previously. In human tissues, sources of ROS production include the NADPH oxidases (NOX), xanthine oxidize (XO), arachidonic acid metabolism pathways (12/15 lipoxygenase), uncoupled nitric oxide synthase (NOS), and the mitochondrial electron transport system. A large body of evidence suggests that NOX and NOS, along with an oxygen-starved mitochondrial electron transport system, comprise the major sources of ROS in the brain during hypoxia and ischemia.

After a hypoxic-ischemic attack, resident immune cells in the brain are stimulated. They generate several oxygen free radicals and then induce the expression of pro-inflammatory mediators. These superoxide (including superoxide anions (O2·−), hydrogen peroxide (H2O2), hypochlorous acid and hydroxyl radicals (·OH) O2·−) are generated via several enzyme systems, including NADPH oxidase, glutathione peroxidase (GPX), cyclooxygenase (COX), xanthine dehydrogenase, XO, monoamine oxidase (MAO), and myeloperoxidase (MPO). However, the role of NADPH oxidase, the most important source of ROS, in neonatal inflammatory responses following hypoxic-ischemic attack is controversial. On the one hand, inhibition of NADPH oxidase increases the level of inflammation cytokines, however, by comparison, in vivo studies have showed that it can exacerbate inflammatory responses and worsen neurological outcomes in animal models.

3. Clinical Manifestations and Potential Biomarkers for Hypoxic-Ischemic Encephalopathy (HIE)

During and after exposure to HIE, neural imaging, electroencephalography (EEG), and biochemical markers have been used to assess prognosis and predict long-term outcomes, such as visual impairment, learning impairment, epilepsy, mental retardation, blindness, cerebral palsy, and even death. As the spectrum of imaging findings relates to the evolution of ischemic parenchymal tissue (basal ganglia and thalami, corticospinal tract, white matter, and cortex), magnetic resonance image (MRI) is the preferred imaging choice. Doppler sonography is also sensitive in the detection of HIE. Because of the high water content in the brain, and high protein content of the cerebrospinal fluid, which results in poor parenchyma contrast resolution, computed tomography (CT) is the least sensitive modality for the evaluation of HIE. Like imaging techniques, EEG can be readily measured at the bedside. The most promising EEG features in identifying HIE include burst suppression, low voltage, and a flat trace. Various numbers of biochemical markers in body fluids have also been suggested to be useful as sentinel biomarkers, including S100B, neuron-specific enolase (NSE), miRNA, lactate dehydrogenase (LDH), adrenomedullin, activin A, Tau protein, non-protein bound iron, serum CD4 cell count, nuclear factor-κB (NF-κB), ionized calcium, creatine kinase (CK-BB), carboxyl-terminal esterase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), and interleukins, IL-6, IL-8, and IL-1β.

4.1. Inflammation-Mediated Oxidative Stress in HIE

Both clinical and experimental studies suggest that oxidative stress plays a role in crosstalk between inflammatory systems and creates “windows of susceptibility” to HIE. Two phases of HIE-induced oxidative stress mediated by inflammatory responses have been identified. In the initial step, inflammation is activated by amoeboid microglia, the resident immune cell in the brain. Microglia respond vigorously to hypoxic-ischemic attack and produce excess inflammatory cytokines (IL-1β, TNF-α, etc.) along with glutamate, nitric oxide (NO), and ROS. Alongside microglia, astrocytes are also activated by ROS, and secrete pro-inflammatory cytokines (IL-6, TNF-α, IL-1α, and IL-1β) and IFN-γ. Rapid increases in the levels of these cytokines cause collective accumulation in the brain tissue, leading to direct injury through increasing levels of toxic NO, inducing the apoptosis of neuronal cells, inhibiting neurogenesis, and attracting immune cells to the ischemic site. Brain tissue injury is exacerbated by the complex interaction between neutrophils, lymphocytes, adhesion molecules, cytokines, and chemokines. During ischemia, neutrophils can amplify brain injury through inducing ROS production. Interestingly, however, studies have shown that lymphocytes play a negative role in the pathogenesis of the acute ischemic brain. The main cytokines relating to the inflammatory responses seen in HIE are IL-1, IL-6, IL-10, TNF-α, and TGF-β, with high levels of these cytokines under oxidative stress correlating positively with HIE severity.

4.2. Mitochondrial Injury in HIE

Mitochondria function as “power houses”, generating adenosine triphosphate (ATP), and serve as the major sites of oxidative metabolism. During HIE, oxidative stress caused by ROS “bursts” plays an important role in changes in the mitochondria, including ischemic starvation, reperfusion-induced hyper activation, mitochondrial dysfunction, and delayed neuronal death. Initially, during oxidation associated with mitochondrial respiration, the mitochondrial membrane potential (ΔΨm) becomes positive in the inner chamber, in contrast to physiological conditions. Secondly, there is an increase of intracellular Ca2+, with decreasing glucose and ATP generation, and cytochrome c (CytC) releases into the cytoplasm. During HIE, the release of CytC from the mitochondrial serves as a rather important pathway for the cascades of apoptotic events. First, loosely-coupled or tightly-bound CytC is damaged in the mitochondrial membrane and then released; second, pro-apoptotic proteins, Bid, Bad, Bax, Bak, Bok, and Bim in the outer mitochondrial membrane increase the permeability of the membrane, forming specific pores and stimulating free CytC release; third, CytC binds to apoptosis protein-associated factor 1 (Apaf-1) and forms the Apaf-1/caspase-9/CytC complex. Finally, caspase-3 is activated, which triggers apoptosis and delayed neuronal death.

4.3. Oxidative Stress Mediated Apoptosis in HIE

Apoptosis, the process of programmed cell death, is a series of well-coordinated and strictly controlled processes leading to cell blebbing, shrinkage, nuclear fragmentation, chromatin condensation, proteolysis, and chromosomal DNA fragmentation. Apoptosis occurs in a wide variety of physiological and pathological situations. In recent years, ROS have become a target for drug discovery since their production is characteristic of the early stages of apoptosis preceding the collapse of the mitochondrial membrane potential, release of pro-apoptotic factors, and activation of caspases. Oxidative stress-mediated apoptosis in HIE can occur via extrinsic and intrinsic pathways. In extracellular apoptotic signaling, inflammatory markers (such as TNF-α, TRAIL, Apo3L, and Fas ligand (Fas-L)) respond to HIE, activate NF-κB, bind to their receptors, lead to caspase-8 activation and the cleavage of the pro-apoptotic Bcl-2 family protein Bid to t-Bid, and finally induce both apoptosis and cell survival triggering intrinsic signals. Oxidative stress-mediated mitochondrial injury appears to be mainly involved in the intracellular apoptotic signaling. The first mechanism is mediated by intermembrane space proteins, such as CytC, apoptosis inducing factor (AIF), Endo G and Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with a low pI), released into the cytosol. The second mechanism is mediated by proteins of the Bcl-2 family acting directly on the outer mitochondrial membrane.

4.4. Oxidative Stress Mediated Autophagy in HIE

Autophagy, or type-II programmed cell death, is a conserved, intracellular, lysosome-dependent degradation process that recycles defective proteins or damaged organelles. Autophagy is up-regulated in response to oxidative stress, helping to restore intracellular homeostasis by disposing a number of harmful molecules such as misfolded proteins overflowing from endoplasmic reticulum (ER) stress, cytosolic proteins damaged by ROS, or even dysfunctional mitochondria or ER from prolonged oxidative stress. The autophagy pathway can induce IKKα/NF-κB/I-κB kinase β-mediated pro-inflammatory signaling via the oxidative stress pathway. In parallel, when homeostasis of ROS is disrupted, excessive ROS are accumulated in the mitochondria and cytoplasm and can cause oxidative damage to cells and induce autophagy. ROS-mediated molecular networks, such as PI3K-Akt-mTOR, TLR-4, IGF, MAPK, and AMPK, depend on several distinct mechanisms involving catalase or caspase activation of autophagy-related genes, and disturbances in the mitochondrial electron transport chain. However, oxidative stress-mediated autophagy in HIE remains controversial, and whether there is a beneficial or detrimental role of autophagy depends on whether intracellular stresses have been resolved.

5. Clinical Strategies of Antioxidants in HIE

Over the past decade, hypothermia has been established as the standard treatment for HIE, and further investigation for a multi-targeted approach has yet to be researched in depth. Interventional targets have consisted of pathways involved in inflammation, apoptosis, and autophagy followed by oxidative stress in experimental translational studies (Figure 1).

5.1. Hypothermia

Hypothermia is routinely used as a protective therapeutic tool for moderate to severe HIE in clinical application. Selective head cooling (34.5 °C) and total body cooling (33.5 °C) are the two therapeutic hypothermia methods. The decrease in temperature affects all physiological systems of the body, including redistribution of blood flow and disturbances of microcirculation, eventually leading to the reduction of metabolism and oxygen supply to tissues. When hypothermia is used in HIE it maintains or improves the level of antioxidants. Therapeutic hypothermia must begin within the first six hours after birth, and be maintained for three days. Studies have shown that this treatment is effective for reducing cerebral injury and improves the brain outcome secondary to hypoxic-ischemic attack in full-term-born and near-term preterm newborns.

5.2. Erythropoietin (EPO)

There is compelling preclinical research and clinical evidence that(EPO) can promote the expression of anti-apoptotic genes relative to pro-apoptotic genes, inhibit inflammation, attenuate oxygen free radicals, decrease caspase activation, and increase neurogenesis in response to HIE through the cross talk between PI3K/AKT, STAT5, and ERK molecular signal pathway. Currently there are two active clinical trials (Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes in Newborn Brain Injury (NCT01913340) and Efficacy of Erythropoietin to Improve Survival and Neurological Outcome in Hypoxic Ischemic Encephalopathy (NCT01732146)) examining EPO in combination with hypothermia in infants with HIE. The NCT01913340 assesses an EPO dose of 1000 U/kg/dose IV × 5 doses, while the NCT01732146 evaluates EPO intravenous injections (5000 U/0.3 mL) 1000 to 1500 U/kg/dose three times given every 24 h with the first dose within 12 h of delivery. Studies have shown that EPO administration is safe in both the adult and neonatal brain. Combining cooling with EPO in HIE could improve the recovery of sensor motor function, behavioral and cognitive performance, and histological integrity, improve motor and cognitive responses, promote cerebella growth, and reduce death or disability.

5.3. N-Acetyl-5-methoxytryptamine (Melatonin)

Melatonin, a strong endogenous indolamine, has shown a neuroprotective role. Melatonin, has anti-inflammatory, antioxidant, and anti-apoptotic properties in HIE. Melatonin′s protective actions are believed to stem from the interaction of its receptors (receptor dependent actions), its direct free radical scavenging (receptor-independent actions), and because of yet-undefined functions. Melatonin freely crosses the placenta and blood-brain barrier making it more attractived. A previous study has shown that pretreated melatonin in asphyxiated term neonates (received hypothermia combined application with melatonin 10 mg/kg × 5 days, oral.) is feasible and may ameliorate brain injury. It is likely that higher doses are required to obtain an antioxidant effect and this high dose might even desensitize the melatonin receptors.

5.4. N-Acetylserotonin (NAS)

NAS has also been shown to be better as scavenging peroxyl radicals than melatonin itself. The neuroprotective effects of NAS in HIE may result through its effects on cells mitochondrial impairment, including permeability transition pore opening, fragmentation, inhibition of the subsequent release of apoptogenic factors from mitochondria into the cytoplasm, activation of apoptosis protein expression, as well as suppression of the activation of autophagy under oxidative stress conditions.

5.5. Magnesium Sulfate (MgSO4)

A lot of interesting research shows that MgSO4 can reduce secondary inflammation and associated injury that occurs under oxidative stress. The possible mechanism may be mainly due to the fact that MgSO4 can bind to the magnesium site on N-methyl-d-aspartate (NMDA) glutamate channels, inhibiting free radical production, and stabilizing the cell membrane. There is now evidence from meta-analyses of randomized controlled trials that antenatal administration of MgSO4 is associated with a small but significant reduction in the risk of cerebral palsy and gross motor dysfunction after preterm birth. However, it has no significant effect on death or disability.

5.6. Stem Cells

Combined treatment with hypothermia and transplantation stem cells (e.g., amnion epithelial cells (AECs), hematopoietic stem cells (HSC), umbilical cord blood (UCB), UCB-derived endothelial progenitor cells (EPCs), and bone marrow-derived mesenchymal stem cells (MSCs)) has been regarded as a therapeutic strategy to promote functional recovery in animal models of HIE. A previous study has shown that the collection, preparation, and infusion of fresh autologous UCB cells for use in infants with HIE is feasible. In addition to stem cell transplantation, there is ongoing research in the field of stem cell factors (e.g., G-CSF).

5.7. Edaravone (3-Methyl-1-phenyl-2-pyrazolin-5-one)

Edaravone is a free radical scavenger that is thought to be useful in the treatment of post-ischemic neuronal dysfunction, and improving memory and learning ability in HIE. Using brain microdialysis, electron paramagnetic resonance (EPR) spectroscopy, photo acoustic imaging, and laser speckle contrast imaging detection, research on edaravone has indicated that it is believed to interact with peroxyl and hydroxyl radicals, lipid peroxidation, and DNA peroxidation, and that it creates a radical intermediate that forms stable oxidation products. Clinical studies show that, in the treatment group treated with edaravone alone or in combination which other neuroprotective drugs (such as Ganglioside, hyperbaric oxygen (HBO), Xingnaojing, etc.) the difference of national institutes of health stroke scale (NIHSS), proinflammatory, anti-inflammatory cytokines, free radicals was statistically significant.

5.8. Allopurinol

Evidence exists that suggest that allopurinol, a xanthine-oxidase inhibitor, functions as a chelator of non-protein bound iron, as well as a direct scavenger of free radicals, suggesting that allopurinol may be an adjunct to therapeutic hypothermia in HIE. In a recent study, treatment with allopurinol in HIE infants with hypoplastic left heart syndrome significantly impeded the biochemical cascade of neuronal damage, including seizures, death, coma or cardiac events, in comparison to a control group.

5.9. Osteopontin (OPN)

Recent studies show that OPN, a multifunctional glycoprotein, is up-regulated in brain tissue affected by HIE. Exogenous OPN has decreased infarct volume and improved neurological outcomes. OPN-induced neuroprotection was associated with cleaved caspase-3 inhibition, regulation of cerebral cell proliferation, oligodendrocyte differentiation, and anti-apoptotic cell death.

5.10. Flunarizine

Flunarizine, a selective Ca2+ channel blocker, which has potent neuroprotective properties against hypoxic-ischemic encephalopathy, acts according to a mechanism independent of effects on dopamine release.

5.11. Nitric Oxide

Inducible NO synthase (iNOS) is induced to produce excessive NO in which leads to cascade reactions of inflammation and neuronal death in HIE. Nitric oxide, an iNOS inhibitor, via the NF-κB/nNOS pathway plays a neuroprotective role by increasing iron deposition, inhibiting platelet and leukocyte adhesion, maintaining cerebral blood flow, and preventing neuronal injury. NO has been shown to be a new therapeutic agent in the treatment of brain hypoxia-ischemia.

5.12. Hydrogen Peroxide (H2O2)

Most reviewed studies demonstrate that H2O2, either in the gas or liquid form, acts as a treatment for hypoxia/ischemia through preconditioning protection. Assessed by 2,3,5-triphenyltetrazoliumchloride (TTC), Nissl and TUNEL staining, and caspase-3 and caspase-12 activities in the cortex and hippocampus, H2O2 may act via theHIF-1α pathway inhibiting neuronal apoptosis and attenuating cerebrovascular reactivity (CR) to hypercapnia, N-methyl-d-aspartate (NMDA), norepinephrine, and sodium nitroprusside.

5.13. Insulin-Like Growth Factor-1 (IGF-1) and the N-Terminal Tripeptide of IGF-1 (GPE)

IGF-1 and GPE is a polypeptide hormone that has been investigated as a potential neurotrophic factor for the treatment of HIE. IGF-1, via the PI3K/Akt/GSK3β and NF-κB pathway phosphorylation, attenuates activation of caspases and mitogenic effects. Previous research has demonstrated that the neuroprotective actions of IGF-1 infusion were global, robust, and displayed a broad effective dose range and treatment window.

5.14. Blockade of Connexin Hemi Channels (Connexons)

Increasing evidence supports that suppressing the induction or activity of the connexin proteins forming hemichannels contributes to HIE. Previous research has revealed that unopposed connexons also play an important role. They mediate the release of paracrine molecules, which in turn transmit cell death messages by the secretion of intracellular mediators (such as ATP, Nicotinamide adenine dinucleotide (NAD+), and glutamate), which ultimately leads to cell edema.

5.15. Naloxone and β-FNA

Naloxone, a µ-opioid receptor blocker, and β-FNA, a µ-opioid receptor antagonist, both attenuate myeloperoxidase activity and chemokine (macrophage inflammatory protein-1 alpha and -2) mRNA expression via C-fos, C-jun, Nur77, and the MAPK pathway in HIE.

5.16. Salvia

Studies have shown that Endothelin-1 (ET-1), NO, and CK-BBin in both the blood and cerebrospinal fluid (CSF) participated in the pathological process and determine the therapeutic effects of HIE. Salvia injection demonstrated a therapeutic effect superior to a control group at a statistically significant level.

5.17. Other Traditional Chinese Medicines and Related Extracts

This group includes examples such as paeoniflorin, xinnaoxin, astragalus, and safflower, among others.

6. Conclusions

HIE is one of the leading causes of morbidity and mortality in neonates. In this review, we highlighted the molecular mechanism and protection strategies for oxidative stress in HIE, mainly focusing on mechanisms related to anti-inflammation, anti-apoptosis, and regulation of autophagy (Table 1). Therapeutic interventions enabling the prevention or reduction in hypoxia-induced brain damage before or during an early stage of free radical production will require continued investigation to determine optimal effectiveness. Moreover, the safety and efficacy of these combinatorial strategies for HIE can be maximized by following pertinent translational research guidelines.

References 106

  1. 1.

    Allen C.L., Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int. J. Stroke Off. J. Int. Stroke Soc. 2009;4:461-470.

    Not in our library10.1111/j.1747-4949.2009.00387.x

  2. 2.

    Ikonomidou C., Kaindl A.M. Neuronal death and oxidative stress in the developing brain. Antioxid. Redox Signal. 2011;14:1535-1550.

    Not in our library10.1089/ars.2010.3581

  3. 3.

    Doyle K.P., Simon R.P., Stenzel-Poore M.P. Mechanisms of ischemic brain damage. Neuropharmacology. 2008;55:310-318.

    Not in our library10.1016/j.neuropharm.2008.01.005

  4. 4.

    Solovieva E.Y., Chipova D.T. From the conception of “oxidizing stress” to the conception of “cell signaling modulation”. Zh. Nevrol. Psikhiatr. Im. S.S. 2015;115:105-111.

    Not in our library10.17116/jnevro201511581105-111

  5. 5.

    Hole P.S., Darley R.L., Tonks A. Do reactive oxygen species play a role in myeloid leukemias? Blood. 2011;117:5816-5826.

    Not in our library10.1182/blood-2011-01-326025

  6. 6.
    Diabetic Cardiovascular Disease Induced by Oxidative Stress · 2015
    No notice
  7. 7.

    Angeloni C., Prata C., Dalla Sega F.V., Piperno R., Hrelia S. Traumatic brain injury and NADPH oxidase: A deep relationship. Oxid. Med. Cell. Longev. 2015;2015:370312.

    Not in our library10.1155/2015/370312

  8. 8.

    Lu Q., Wainwright M.S., Harris V.A., Aggarwal S., Hou Y., Rau T., Poulsen D.J., Black S.M. Increased NADPH oxidase-derived superoxide is involved in the neuronal cell death induced by hypoxia-ischemia in neonatal hippocampal slice cultures. Free Radic. Biol. Med. 2012;53:1139-1151.

    Not in our library10.1016/j.freeradbiomed.2012.06.012

  9. 9.

    Wei I.H., Huang C.C., Tseng C.Y., Chang H.M., Tu H.C., Tsai M.H., Wen C.Y., Shieh J.Y. Mild hypoxic preconditioning attenuates injury-induced NADPH-d/nNOS expression in brainstem motor neurons of adult rats. J. Chem. Neuroanat. 2008;35:123-132.

    Not in our library10.1016/j.jchemneu.2007.08.008

  10. 10.

    Wang Z., Feng C., Zhao H., Ren X., Peng S., Zuo Z. Autoregulation of inducible nitric oxide synthase expression by RNA interference provides neuroprotection in neonatal rats. Theranostics. 2015;5:504-514.

    Not in our library10.7150/thno.10441

  11. 11.

    Liu H., Li J., Zhao F., Wang H., Qu Y., Mu D. Nitric oxide synthase in hypoxic or ischemic brain injury. Rev. Neurosci. 2015;26:105-117.

    Not in our library10.1515/revneuro-2014-0041

  12. 12.

    Liu Y., Li W., Hu L., Liu Y., Li B., Sun C., Zhang C., Zou L. Downregulation of nitric oxide by electroacupuncture against hypoxicischemic brain damage in rats via nuclear factor κB/neuronal nitric oxide synthase. Mol. Med. Rep. 2015;11:837-842.

    Not in our library10.3892/mmr.2014.2879

  13. 13.

    Yu L., Yi J., Ye G., Zheng Y., Song Z., Yang Y., Song Y., Wang Z., Bao Q. Effects of curcumin on levels of nitric oxide synthase and AQP-4 in a rat model of hypoxia-ischemic brain damage. Brain Res. 2012;1475:88-95.

    Not in our library10.1016/j.brainres.2012.07.055

  14. 14.

    Kuzmanic Samija R., Primorac D., Resic B., Pavlov V., Capkun V., Punda H., Lozic B., Zemunik T. Association of NOS3 gene variants and clinical contributors of hypoxic-ischemic encephalopathy. Braz. J. Med. Biol. Res. Rev. Bras. Pesqui. Med. E Biol. Soc. Bras. Biofisica. 2014;47:869-875.

    Not in our library10.1590/1414-431x20143938

  15. 15.

    Drobyshevsky A., Yu L., Yang Y., Khalid S., Luo K., Jiang R., Ji H., Derrick M., Kay L., Silverman R.B., et al. Antenatal insults modify newborn olfactory function by nitric oxide produced from neuronal nitric oxide synthase. Exp. Neurol. 2012;237:427-434.

    Not in our library10.1016/j.expneurol.2012.07.006

  16. 16.

    Mao P., Ardeshiri A., Jacks R., Yang S., Hurn P.D., Alkayed N.J. Mitochondrial mechanism of neuroprotection by CART. Eur. J. Neurosci. 2007;26:624-632.

    Not in our library10.1111/j.1460-9568.2007.05691.x

  17. 17.

    Jin R., Yang G., Li G. Inflammatory mechanisms in ischemic stroke: Role of inflammatory cells. J. Leukoc. Biol. 2010;87:779-789.

    Not in our library10.1189/jlb.1109766

  18. 18.

    Doverhag C., Keller M., Karlsson A., Hedtjarn M., Nilsson U., Kapeller E., Sarkozy G., Klimaschewski L., Humpel C., Hagberg H., et al. Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice. Neurobiol. Dis. 2008;31:133-144.

    Not in our library10.1016/j.nbd.2008.04.003

  19. 19.

    Tang X.N., Cairns B., Kim J.Y., Yenari M.A. NADPH oxidase in stroke and cerebrovascular disease. Neurol. Res. 2012;34:338-345.

    Not in our library10.1179/1743132812y.0000000021

  20. 20.

    Douglas-Escobar M., Weiss M.D. Hypoxic-ischemic encephalopathy: A review for the clinician. JAMA Pediatr. 2015;169:397-403.

    Not in our library10.1001/jamapediatrics.2014.3269

  21. 21.

    Goergen S.K., Ang H., Wong F., Carse E.A., Charlton M., Evans R., Whiteley G., Clark J., Shipp D., Jolley D., et al. Early MRI in term infants with perinatal hypoxic-ischaemic brain injury: Interobserver agreement and MRI predictors of outcome at 2 years. Clin. Radiol. 2014;69:72-81.

    Not in our library10.1016/j.crad.2013.09.001

  22. 22.

    Rutherford M., Biarge M.M., Allsop J., Counsell S., Cowan F. MRI of perinatal brain injury. Pediatr. Radiol. 2010;40:819-833.

    Not in our library10.1007/s00247-010-1620-z

  23. 23.

    Heinz E.R., Provenzale J.M. Imaging findings in neonatal hypoxia: A practical review. AJR. Am. J. Roentgenol. 2009;192:41-47.

    Not in our library10.2214/ajr.08.1321

  24. 24.

    Awal M.A., Lai M.M., Azemi G., Boashash B., Colditz P.B. EEG background features that predict outcome in term neonates with hypoxic ischaemic encephalopathy: A structured review. Clin. Neurophysiol. Off. J. Int. Fed. Clin. Neurophysiol. 2015;127:285-296.

    Not in our library10.1016/j.clinph.2015.05.018

  25. 25.

    Ramaswamy V., Horton J., Vandermeer B., Buscemi N., Miller S., Yager J. Systematic review of biomarkers of brain injury in term neonatal encephalopathy. Pediatr. Neurol. 2009;40:215-226.

    Not in our library10.1016/j.pediatrneurol.2008.09.026

  26. 26.

    Gazzolo D., Abella R., Marinoni E., di Iorio R., Li Volti G., Galvano F., Frigiola A., Temporini F., Moresco L., Colivicchi M., et al. New markers of neonatal neurology. J. Mater.-Fetal Neonatal Med. Off. J. Eur. Assoc. Perinat. Med. Fed. Asia Ocean. Perinat. Soc. Int. Soc. Perinat. Obstet. 2009;22:57-61.

    Not in our library10.1080/14767050903181468

  27. 27.

    Lv H., Wang Q., Wu S., Yang L., Ren P., Yang Y., Gao J., Li L. Neonatal hypoxic ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid. Clin. Chim. Acta Int. J. Clin. Chem. 2015;450:282-297.

    Not in our library10.1016/j.cca.2015.08.021

  28. 28.

    Kaur C., Rathnasamy G., Ling E.A. Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina. J. Neuroimmune Pharmacol. Off. J. Soc. Neuroimmune Pharmacol. 2013;8:66-78.

    Not in our library10.1007/s11481-012-9347-2

  29. 29.

    Jellema R.K., Lima Passos V., Zwanenburg A., Ophelders D.R., de Munter S., Vanderlocht J., Germeraad W.T., Kuypers E., Collins J.J., Cleutjens J.P., et al. Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep. J. Neuroinflamm. 2013;10:13.

    Not in our library10.1186/1742-2094-10-13

  30. 30.

    Tuttolomondo A., di Raimondo D., di Sciacca R., Pinto A., Licata G. Inflammatory cytokines in acute ischemic stroke. Curr. Pharm. Des. 2008;14:3574-3589.

    Not in our library10.2174/138161208786848739

  31. 31.

    Brait V.H., Jackman K.A., Walduck A.K., Selemidis S., Diep H., Mast A.E., Guida E., Broughton B.R., Drummond G.R., Sobey C.G. Mechanisms contributing to cerebral infarct size after stroke: Gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2010;30:1306-1317.

    Not in our library10.1038/jcbfm.2010.14

  32. 32.

    Wang J., Lu Q. Expression of T subsets and mIL-2R in peripheral blood of newborns with hypoxic ischemic encephalopathy. World J. Pediatr. WJP. 2008;4:140-144.

    Not in our library10.1007/s12519-008-0028-4

  33. 33.

    Becker K.J. Activation of immune responses to brain antigens after stroke. J. Neurochem. 2012;123:148-155.

    Not in our library10.1111/j.1471-4159.2012.07953.x

  34. 34.

    Liu J., Feng Z.C. Increased umbilical cord plasma interleukin-1 β levels was correlated with adverse outcomes of neonatal hypoxic-ischemic encephalopathy. J. Trop. Pediatr. 2010;56:178-182.

    Not in our library10.1093/tropej/fmp098

  35. 35.

    Girard S., Sebire H., Brochu M.E., Briota S., Sarret P., Sebire G. Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries. Brain Behav. Immun. 2012;26:1331-1339.

    Not in our library10.1016/j.bbi.2012.09.001

  36. 36.

    Green H.F., Treacy E., Keohane A.K., Sullivan A.M., O′Keeffe G.W., Nolan Y.M. A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells. Mol. Cell. Neurosci. 2012;49:311-321.

    Not in our library10.1016/j.mcn.2012.01.001

  37. 37.

    Favrais G., van de Looij Y., Fleiss B., Ramanantsoa N., Bonnin P., Stoltenburg-Didinger G., Lacaud A., Saliba E., Dammann O., Gallego J., et al. Systemic inflammation disrupts the developmental program of white matter. Ann. Neurol. 2011;70:550-565.

    Not in our library10.1002/ana.22489

  38. 38.

    Mirabelli-Badenier M., Braunersreuther V., Viviani G.L., Dallegri F., Quercioli A., Veneselli E., Mach F., Montecucco F. CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke. Thromb. Haemost. 2011;105:409-420.

    Not in our library10.1160/th10-10-0662

  39. 39.

    Ablikim M., Achasov M.N., Ai X.C., Albayrak O., Albrecht M., Ambrose D.J., An F.F., An Q., Bai J.Z., Baldini Ferroli R., et al. Observation of eta′-->pi+ pi pi+ pi- and eta′-->pi+ pi- pi0 pi0. Phys. Rev. Lett. 2014;112:251801.

    Not in our library10.1103/physrevlett.112.251801

  40. 40.

    Acin-Perez R., Hoyos B., Gong J.L., Vinogradov V., Fischman D.A., Leitges M., Borhan B., Starkov A., Manfredi G., Hammerling U. Regulation of intermediary metabolism by the PKCδ signalosome in mitochondria. FASEB J. 2010;24:5033-5042.

    Not in our library10.1096/fj.10-166934

  41. 41.

    Sanderson T.H., Reynolds C.A., Kumar R., Przyklenk K., Huttemann M. Molecular mechanisms of ischemia-reperfusion injury in brain: Pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol. Neurobiol. 2013;47:9-23.

    Not in our library10.1007/s12035-012-8344-z

  42. 42.

    Nakka V.P., Gusain A., Mehta S.L., Raghubir R. Molecular mechanisms of apoptosis in cerebral ischemia: Multiple neuroprotective opportunities. Mol. Neurobiol. 2008;37:7-38.

    Not in our library10.1007/s12035-007-8013-9

  43. 43.

    Hardwick J.M., Chen Y.B., Jonas E.A. Multipolar functions of BCL-2 proteins link energetics to apoptosis. Trends Cell Biol. 2012;22:318-328.

    Not in our library10.1016/j.tcb.2012.03.005

  44. 44.

    Orrenius S., Gogvadze V., Zhivotovsky B. Mitochondrial oxidative stress: Implications for cell death. Annu. Rev. Pharmacol. Toxicol. 2007;47:143-183.

    Not in our library10.1146/annurev.pharmtox.47.120505.105122

  45. 45.
    Oxidative stress-mediated HMGB1 biology · 2015
    No notice
  46. 46.

    Kroemer G., Galluzzi L., Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 2007;87:99-163.

    Not in our library10.1152/physrev.00013.2006

  47. 47.

    Bayir H., Kagan V.E. Bench-to-bedside review: Mitochondrial injury, oxidative stress and apoptosis—There is nothing more practical than a good theory. Crit. Care. 2008;12:206.

    Not in our library10.1186/cc6779

  48. 48.

    Wang P., Miao C.Y. Autophagy in the disorders of central nervous system: Vital and/or fatal? CNS Neurosci. Ther. 2012;18:955-956.

    Not in our library10.1111/cns.12024

  49. 49.

    Wei K., Wang P., Miao C.Y. A double-edged sword with therapeutic potential: An updated role of autophagy in ischemic cerebral injury. CNS Neurosci. Ther. 2012;18:879-886.

    Not in our library10.1111/cns.12005

  50. 50.

    Singh R., Kaushik S., Wang Y., Xiang Y., Novak I., Komatsu M., Tanaka K., Cuervo A.M., Czaja M.J. Autophagy regulates lipid metabolism. Nature. 2009;458:1131-1135.

    Not in our library10.1038/nature07976

  51. 51.

    Gonzalez C.D., Lee M.S., Marchetti P., Pietropaolo M., Towns R., Vaccaro M.I., Watada H., Wiley J.W. The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy. 2011;7:2-11.

    Not in our library10.4161/auto.7.1.13044

  52. 52.

    Zhou R., Yazdi A.S., Menu P., Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221-225.

    Not in our library10.1038/nature09663

  53. 53.

    Hall J.C., Crawford H.C. The conspiracy of autophagy, stress and inflammation in acute pancreatitis. Curr. Opin. Gastroenterol. 2014;30:495-499.

    Not in our library10.1097/mog.0000000000000097

  54. 54.

    Scherz-Shouval R., Elazar Z. Regulation of autophagy by ROS: Physiology and pathology. Trends Biochem. Sci. 2011;36:30-38.

    Not in our library10.1016/j.tibs.2010.07.007

  55. 55.

    Farooqi A.A., Fayyaz S., Hou M.F., Li K.T., Tang J.Y., Chang H.W. Reactive oxygen species and autophagy modulation in non-marine drugs and marine drugs. Mar. Drugs. 2014;12:5408-5424.

    Not in our library10.3390/md12115408

  56. 56.

    Alva N., Palomeque J., Carbonell T. Oxidative stress and antioxidant activity in hypothermia and rewarming: Can RONS modulate the beneficial effects of therapeutic hypothermia? Oxid. Med. Cell. Longev. 2013;2013:957054.

    Not in our library10.1155/2013/957054

  57. 57.

    Bayir H., Adelson P.D., Wisniewski S.R., Shore P., Lai Y., Brown D., Janesko-Feldman K.L., Kagan V.E., Kochanek P.M. Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children. Crit. Care Med. 2009;37:689-695.

    Not in our library10.1097/ccm.0b013e318194abf2

  58. 58.

    Silveira R.C., Procianoy R.S. Hypothermia therapy for newborns with hypoxic ischemic encephalopathy. J. Pediatr. 2015;91:S78-S83.

    Not in our library10.1016/j.jped.2015.07.004

  59. 59.

    Robertson N.J., Tan S., Groenendaal F., van Bel F., Juul S.E., Bennet L., Derrick M., Back S.A., Valdez R.C., Northington F., et al. Which neuroprotective agents are ready for bench to bedside translation in the newborn infant? J. Pediatr. 2012;160:544-552.

    Not in our library10.1016/j.jpeds.2011.12.052

  60. 60.

    Park M.H., Lee S.M., Lee J.W., Son D.J., Moon D.C., Yoon D.Y., Hong J.T. ERK-mediated production of neurotrophic factors by astrocytes promotes neuronal stem cell differentiation by erythropoietin. Biochem. Biophys. Res. Commun. 2006;339:1021-1028.

    Not in our library10.1016/j.bbrc.2005.10.218

  61. 61.

    Lee S.T., Chu K., Sinn D.I., Jung K.H., Kim E.H., Kim S.J., Kim J.M., Ko S.Y., Kim M., Roh J.K. Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage. J. Neurochem. 2006;96:1728-1739.

    Not in our library10.1111/j.1471-4159.2006.03697.x

  62. 62.

    Shankaran S. Outcomes of hypoxic-ischemic encephalopathy in neonates treated with hypothermia. Clin. Perinatol. 2014;41:149-159.

    Not in our library10.1016/j.clp.2013.10.008

  63. 63.

    Elmahdy H., El-Mashad A.R., El-Bahrawy H., El-Gohary T., El-Barbary A., Aly H. Human recombinant erythropoietin in asphyxia neonatorum: Pilot trial. Pediatrics. 2010;125:e1135-e1142.

    Not in our library10.1542/peds.2009-2268

  64. 64.

    Traudt C.M., McPherson R.J., Bauer L.A., Richards T.L., Burbacher T.M., McAdams R.M., Juul S.E. Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev. Neurosci. 2013;35:491-503.

    Not in our library10.1159/000355460

  65. 65.

    Fang A.Y., Gonzalez F.F., Sheldon R.A., Ferriero D.M. Effects of combination therapy using hypothermia and erythropoietin in a rat model of neonatal hypoxia-ischemia. Pediatr. Res. 2013;73:12-17.

    Not in our library10.1038/pr.2012.138

  66. 66.

    Fan X., van Bel F., van der Kooij M.A., Heijnen C.J., Groenendaal F. Hypothermia and erythropoietin for neuroprotection after neonatal brain damage. Pediatr. Res. 2013;73:18-23.

    Not in our library10.1038/pr.2012.139

  67. 67.

    Alonso-Alconada D., Alvarez A., Arteaga O., Martinez-Ibarguen A., Hilario E. Neuroprotective effect of melatonin: A novel therapy against perinatal hypoxia-ischemia. Int. J. Mol. Sci. 2013;14:9379-9395.

    Not in our library10.3390/ijms14059379

  68. 68.

    Carloni S., Perrone S., Buonocore G., Longini M., Proietti F., Balduini W. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J. Pineal Res. 2008;44:157-164.

    Not in our library10.1111/j.1600-079x.2007.00503.x

  69. 69.

    Robertson N.J., Faulkner S., Fleiss B., Bainbridge A., Andorka C., Price D., Powell E., Lecky-Thompson L., Thei L., Chandrasekaran M., et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain J. Neurol. 2013;136:90-105.

    Not in our library10.1093/brain/aws285

  70. 70.

    Aly H., Elmandy H., El-Dib M., Rowisha M., Awny M., El-Gohary T., Elbatcht M., Hamisa M., El-Mashad A.R. Melatonin use for neuroprotection in perinatal asphyxia: A randomized controlled pilot study. J. Perinatol. 2015;35:186-191.

    Not in our library10.1038/jp.2014.186

  71. 71.

    Zhou H., Wang J., Jiang J., Stavrovskaya I.G., Li M., Li W., Wu Q., Zhang X., Luo C., Zhou S., et al. N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury. J. Neurosci. Off. J. Soc. Neurosci. 2014;34:2967-2978.

    Not in our library10.1523/jneurosci.1948-13.2014

  72. 72.

    Westermaier T., Stetter C., Vince G.H., Pham M., Tejon J.P., Eriskat J., Kunze E., Matthies C., Ernestus R.I., Solymosi L., et al. Prophylactic intravenous magnesium sulfate for treatment of aneurysmal subarachnoid hemorrhage: A randomized, placebo-controlled, clinical study. Crit. Care Med. 2010;38:1284-1290.

    Not in our library10.1097/ccm.0b013e3181d9da1e

  73. 73.

    Cetinkaya M., Alkan T., Ozyener F., Kafa I.M., Kurt M.A., Koksal N. Possible neuroprotective effects of magnesium sulfate and melatonin as both pre- and post-treatment in a neonatal hypoxic-ischemic rat model. Neonatology. 2011;99:302-310.

    Not in our library10.1159/000320643

  74. 74.

    Haramati O., Mane R., Molczadzki G., Perez-Polo J.R., Chalifa-Caspi V., Golan H.M. Magnesium sulfate treatment alters fetal cerebellar gene expression responses to hypoxia. Int. J. Dev. Neurosci. Off. J. Int. Soc. Dev. Neurosci. 2010;28:207-216.

    Not in our library10.1016/j.ijdevneu.2009.11.001

  75. 75.

    Pazaiti A., Soubasi V., Spandou E., Karkavelas G., Georgiou T., Karalis P., Guiba-Tziampiri O. Evaluation of long-lasting sensorimotor consequences following neonatal hypoxic-ischemic brain injury in rats: The neuroprotective role of MgSO4. Neonatology. 2009;95:33-40.

    Not in our library10.1159/000151753

  76. 76.

    Doyle L.W., Crowther C.A., Middleton P., Marret S. Antenatal magnesium sulfate and neurologic outcome in preterm infants: A systematic review. Obstet. Gynecol. 2009;113:1327-1333.

    Not in our library10.1097/aog.0b013e3181a60495

  77. 77.

    Conde-Agudelo A., Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks′ gestation: A systematic review and metaanalysis. Am. J. Obstet. Gynecol. 2009;200:595-609.

    Not in our library10.1016/j.ajog.2009.04.005

  78. 78.

    Cotten C.M., Murtha A.P., Goldberg R.N., Grotegut C.A., Smith P.B., Goldstein R.F., Fisher K.A., Gustafson K.E., Waters-Pick B., Swamy G.K., et al. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J. Pediatr. 2014;164:973-979.

    Not in our library10.1016/j.jpeds.2013.11.036

  79. 79.

    Doycheva D., Shih G., Chen H., Applegate R., Zhang J.H., Tang J. Granulocyte-colony stimulating factor in combination with stem cell factor confers greater neuroprotection after hypoxic-ischemic brain damage in the neonatal rats than a solitary treatment. Transl. Stroke Res. 2013;4:171-178.

    Not in our library10.1007/s12975-012-0225-2

  80. 80.

    Cameron S.H., Alwakeel A.J., Goddard L., Hobbs C.E., Gowing E.K., Barnett E.R., Kohe S.E., Sizemore R.J., Oorschot D.E. Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia. Mol. Cell. Neurosci. 2015;68:56-72.

    Not in our library10.1016/j.mcn.2015.03.019

  81. 81.

    Gonzales-Portillo G.S., Reyes S., Aguirre D., Pabon M.M., Borlongan C.V. Stem cell therapy for neonatal hypoxic-ischemic encephalopathy. Front. Neurol. 2014;5:147.

    Not in our library10.3389/fneur.2014.00147

  82. 82.

    Park W.S., Sung S.I., Ahn S.Y., Yoo H.S., Sung D.K., Im G.H., Choi S.J., Chang Y.S. Hypothermia augments neuroprotective activity of mesenchymal stem cells for neonatal hypoxic-ischemic encephalopathy. PLoS ONE. 2015;10:e0120893.

    Not in our library10.1371/journal.pone.0120893

  83. 83.

    Noor J.I., Ueda Y., Ikeda T., Ikenoue T. Edaravone inhibits lipid peroxidation in neonatal hypoxic-ischemic rats: An in vivo microdialysis study. Neurosci. Lett. 2007;414:5-9.

    Not in our library10.1016/j.neulet.2006.10.024

  84. 84.

    Takizawa Y., Miyazawa T., Nonoyama S., Goto Y., Itoh M. Edaravone inhibits DNA peroxidation and neuronal cell death in neonatal hypoxic-ischemic encephalopathy model rat. Pediatr. Res. 2009;65:636-641.

    Not in our library10.1203/pdr.0b013e3181a16a9f

  85. 85.

    Yoshida H., Mimura J., Imaizumi T., Matsumiya T., Ishikawa A., Metoki N., Tanji K., Ota K., Hayakari R., Kosaka K., et al. Edaravone and carnosic acid synergistically enhance the expression of nerve growth factor in human astrocytes under hypoxia/reoxygenation. Neurosci. Res. 2011;69:291-298.

    Not in our library10.1016/j.neures.2010.12.016

  86. 86.

    Sun Y.Y., Li Y., Wali B., Li Y., Lee J., Heinmiller A., Abe K., Stein D.G., Mao H., Sayeed I., et al. Prophylactic edaravone prevents transient hypoxic-ischemic brain injury: Implications for perioperative neuroprotection. Stroke J. Cereb. Circ. 2015;46:1947-1955.

    Not in our library10.1161/strokeaha.115.009162

  87. 87.

    Chaudhari T., McGuire W. Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy. Cochrane Database Syst. Rev. 2008;CD006817.

    Not in our library10.1002/14651858.cd006817.pub2

  88. 88.

    Kaandorp J.J., Benders M.J., Rademaker C.M., Torrance H.L., Oudijk M.A., de Haan T.R., Bloemenkamp K.W., Rijken M., van Pampus M.G., Bos A.F., et al. Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study. BMC Pregnancy Childbirth. 2010;10:8.

    Not in our library10.1186/1471-2393-10-8

  89. 89.

    Buonocore G., Turrisi G., Kramer B.W., Balduini W., Perrone S. New Pharmacological approaches in infants with hypoxic-ischemic encephalopathy. Curr. Pharm. Des. 2012;18:3086-3100.

    Not in our library10.2174/1381612811209023086

  90. 90.

    Chaudhari T., McGuire W. Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy. Cochrane Database Syst. Rev. 2012;7:CD006817.

    Not in our library10.1002/14651858.cd006817.pub3

  91. 91.

    Legido A., Valencia I., Katsetos C.D., Delivoria-Papadopoulos M. Neuroprotection in perinatal hypoxic-ischemic encephalopathy. Effective treatment and future perspectives. Med. B. Aire. 2007;67:543-555.

    Not in our library

  92. 92.

    Ishijima M., Tsuji K., Rittling S.R., Yamashita T., Kurosawa H., Denhardt D.T., Nifuji A., Ezura Y., Noda M. Osteopontin is required for mechanical stress-dependent signals to bone marrow cells. J. Endocrinol. 2007;193:235-243.

    Not in our library10.1677/joe.1.06704

  93. 93.

    Yumoto K., Nifuji A., Rittling S.R., Tsuchiya Y., Kon S., Uede T., Denhardt D.T., Hemmi H., Notomi T., Hayata T., et al. Osteopontin deficiency suppresses tumor necrosis factor-α-induced apoptosis in chondrocytes. Cartilage. 2012;3:79-85.

    Not in our library10.1177/1947603511421502

  94. 94.

    Bonestroo H.J., Nijboer C.H., van Velthoven C.T., van Bel F., Heijnen C.J. The neonatal brain is not protected by osteopontin peptide treatment after hypoxia-ischemia. Dev. Neurosci. 2015;37:142-152.

    Not in our library10.1159/000369093

  95. 95.

    Gunn A.J., Williams C.E., Mallard E.C., Tan W.K., Gluckman P.D. Flunarizine, a calcium channel antagonist, is partially prophylactically neuroprotective in hypoxic-ischemic encephalopathy in the fetal sheep. Pediatr. Res. 1994;35:657-663.

    Not in our library10.1203/00006450-199406000-00007

  96. 96.

    Liu H.T., Mu D.Z. Inducible nitric oxide synthase and brain hypoxic-ischemic brain damage. Chin. J. Contemp. Pediatr. 2014;16:962-967.

    Not in our library

  97. 97.

    Lu Q., Harris V.A., Rafikov R., Sun X., Kumar S., Black S.M. Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism. Redox Biol. 2015;6:112-121.

    Not in our library10.1016/j.redox.2015.06.007

  98. 98.

    Chang S., Jiang X., Zhao C., Lee C., Ferriero D.M. Exogenous low dose hydrogen peroxide increases hypoxia-inducible factor-1α protein expression and induces preconditioning protection against ischemia in primary cortical neurons. Neurosci. Lett. 2008;441:134-138.

    Not in our library10.1016/j.neulet.2008.06.005

  99. 99.

    Cai J., Kang Z., Liu W.W., Luo X., Qiang S., Zhang J.H., Ohta S., Sun X., Xu W., Tao H., et al. Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci. Lett. 2008;441:167-172.

    Not in our library10.1016/j.neulet.2008.05.077

  100. 100.

    Cai J., Kang Z., Liu K., Liu W., Li R., Zhang J.H., Luo X., Sun X. Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res. 2009;1256:129-137.

    Not in our library10.1016/j.brainres.2008.11.048

  101. 101.

    Eckermann J.M., Krafft P.R., Shoemaker L., Lieberson R.E., Chang S.D., Colohan A. Potential application of hydrogen in traumatic and surgical brain injury, stroke and neonatal hypoxia-ischemia. Med. Gas Res. 2012;2:11.

    Not in our library10.1186/2045-9912-2-11

  102. 102.

    Lin S., Rhodes P.G., Cai Z. Whole body hypothermia broadens the therapeutic window of intranasally administered IGF-1 in a neonatal rat model of cerebral hypoxia-ischemia. Brain Res. 2011;1385:246-256.

    Not in our library10.1016/j.brainres.2011.02.013

  103. 103.

    Davidson J.O., Rout A.L., Wassink G., Yuill C.A., Zhang F.G., Green C.R., Bennet L., Gunn A.J. Non-additive effects of delayed connexin hemichannel blockade and hypothermia after cerebral ischemia in near-term fetal sheep. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2015;35:2052-2061.

    Not in our library10.1038/jcbfm.2015.171

  104. 104.

    Davidson J.O., Green C.R., Bennet L., Nicholson L.F., Danesh-Meyer H., O’Carroll S.J., Gunn A.J. A key role for connexin hemichannels in spreading ischemic brain injury. Curr. Drug Targets. 2013;14:36-46.

    Not in our library10.2174/138945013804806479

  105. 105.

    Huang H.M., Yu J.Y., Ou H.C., Jeng K.C. Effect of naloxone on the induction of immediately early genes following oxygen- and glucose-deprivation in PC12 cells. Neurosci. Lett. 2008;438:252-256.

    Not in our library10.1016/j.neulet.2008.04.036

  106. 106.

    Jiang F.X., Wang S.J., Zhong L. Clinical observation of compound Salvia injection in treating mid-severe infantile hypoxic-ischemic encephalopathy. Chin. J. Integr. Tradit. West. Med. 2001;21:903-905.

    Not in our library

Cited by papers we hold 1

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.