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Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

Souhel Najjar, Daniel M Pearlman, Orrin Devinsky and 2 more

Journal of Neuroinflammation · 2013 · Review

doi:10.1186/1742-2094-10-142

Abstract

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer's disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

1Major depressive disorder (MDD) is the second leading global cause of years lived with disability, with about one-third of patients with MDD failing two or more conventional antidepressant drug trials within the first year of treatment. Current evidence suggests that the pathophysiology of MDD is multifactorial, involving heterogeneous and inter-related mechanisms that affect genetic, neurotransmitter, immune, oxidative, and inflammatory systems. Supporting this interpretation, whereas biomarkers for individual abnormalities possess limited predictive validity for MDD, the predictive validity of several composite biomarker assays is particularly high. For example, one study of 36 patients with MDD showed that a compositive biomarker test—comprising nine individual biomarker assays (α1 antitrypsin, apolipoprotein CIII, myeloperoxidase, soluble tumor necrosis factor α (TNFα) receptor type II, epidermal growth factor, cortisol, brain-derived neurotropic factor, prolactin, and resistin)—had 91.7% sensitivity and 81.3% specificity for MDD. A follow-up study involving a distinct sample of 34 MDD patients and using the same composite assay, replicated these results with a high degree of precision: 91.1% sensitivity, 81.0% specificity.

2Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD (recently reviewed by our group). Neuropathological studies comparing brain tissue from individuals with MDD to that from non-depressed controls have documented associations between MDD and (a) decreased levels of antioxidants, such as glutathione and (b) increased levels of lipid peroxidation end products, such as 4-hydroxy-2-nonenal. Studies assessing peripheral markers of oxidative stress have reported similar findings, including: (a) altered activity of antioxidant enzymes, such as glutathione peroxidase, catalase, superoxide dismutase 1, (b) increased activity of pro-oxidant enzymes such as, xanthine oxidase, (c) increased activity of inducible nitric oxide synthase (iNOS) in leukocytes, (d) increased levels of superoxide (O2-), and (e) increased levels of 8-hydroxy-2-deoxyguanosine (a marker for oxidative damage to DNA). Evidence deriving from genetic, neuropathological, cerebrospinal fluid, and serum studies in humans with MDD and from animal models of depressive-like behavior and chronic stress reveal numerous neuroinflammatory abnormalities in MDD, including: (a) microglial activation, (b) astroglial loss and activation, (c) upregulated ratios of T helper 1 (Th1) cells and proinflammatory cytokines, and (d) decreased CD4+CD25+FOXP3+ regulatory T (TReg) cell counts. Both oxidative stress and neuroinflammation may contribute to decreased serotonergic and increased glutamatergic tone, and increased glutamatergic tone may in turn contribute to oxidative stress and neuroinflammation in a positive feedback loop. In addition, experimental evidence suggests that increased reactive oxygen species (ROS) synthesis (oxidative stress) and neuroinflammation themselves exhibit a bidirectional relationship (Figure 1). Indeed, ROS can activate microglia and increase proinflammatory cytokine synthesis—for example, by stimulating transcription factor nuclear factor κB (NFκB)—whereas activated microglia and proinflammatory cytokines can in turn perpetuate oxidative stress.

3Collectively, data from postmortem neuropathological human studies and in vivo neuroimaging human and animal studies provide strong evidence of neurovascular unit dysfunction with blood-brain barrier (BBB) hyperpermeability in association with oxidative stress and neuroinflammation in selected neurological disorders, such as stroke, epilepsy, Alzheimer’s disease, traumatic brain injury, and multiple sclerosis (Table 1). In these disorders, BBB breakdown, oxidative stress, and inflammation are thought to impair neuronal function. MDD, in contrast to other major psychiatric disorders, is frequently comorbid with such neurological disorders as well as disorders characterized by vascular endothelial dysfunction, such as cardiovascular disease and diabetes mellitus. Whether neurovascular dysfunction with BBB hyperpermeability occurs in primary MDD (without neurological comorbidity), however, remains less clear.

4Shalev and colleagues have previously reviewed evidence through 2009 linking BBB hyperpermeability to psychiatric disorders generally. We review emerging clinical and experimental evidence implicating oxidative stress, eNOS uncoupling, and reduced endothelial NO levels in the pathophysiology of peripheral vascular endothelial dysfunction associated with MDD. We present a theoretical integration of human and animal data linking these mechanisms and those involving neuroinflammation to findings suggesting that neurovascular dysfunction can occur in primary MDD. We also discuss putative links between neurovascular dysfunction with BBB hyperpermeability and neuronal signaling abnormalities in MDD.

Neurovascular unit dysfunction

5The neurovascular unit consists of cerebral microvessels, glial cells (astroglia, microglia, oligodendroglia), and neurons. It is the epicenter of several tightly controlled, dynamic, and complex cellular interactions between glia and neurons, and the coupling of neuronal activity with endothelium-dependent cerebral blood flow. Evidence of an association between MDD and neurovascular dysfunction is indirect, deriving primarily from studies assessing peripheral vascular endothelial dysfunction in MDD and from epidemiological data associating MDD with vascular disorders.

6One method for evaluating endothelial dysfunction involves measuring the relative uptake ratio (RUR) of blood flow in the brachial artery after hyperemic challenge via dynamic nuclear imaging. RUR is a measure of the vascular dilatory response whereby a lower RUR implies poorer vascular endothelial function. In a prospective cohort involving 23 patients with MDD, 23 with minor depressive disorder, and 277 non-depressed controls, the mean RUR was significantly lower in participants with MDD (unadjusted mean = 3.13, SD = 1.51) or minor depressive disorder (unadjusted mean = 3.38, SD = 1.00) compared with non-depressed controls (unadjusted mean = 4.22, SD = 1.74) (F = 6.68, P = 0.001). This effect remained statistically significant after adjusting for age, sex, socioeconomic factors, medical comorbidity, and medications (F = 5.19, P = 0.006). One study evaluating endothelial proapoptotic activity, defined as the percentage of apoptotic nuclei in human umbilical vein endothelial cells, found a significantly increased percentage of proapoptotic nuclei in participants with MDD compared with non-depressed controls (4.4% vs 2.3%, P ≤ 0.001). This finding remained statistically significant after adjusting for age and cardiovascular comorbidity.

7Linking vascular endothelial dysfunction to MDD, epidemiological studies reveal a strong and bidirectional association between MDD and medical conditions characterized by vascular endothelial pathology. A recent meta-analysis involving 16,221 study participants found a significantly increased risk of MDD among individuals with major vascular diseases compared with those without vascular disease: diabetes (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.30 to 1.76, P < 0.0005, 15 studies), cardiovascular disease (OR 1.76, 95% CI 1.08 to 1.80, P < 0.0005, 10 studies), and stroke (OR 2.11, 95% CI 1.61 to 2.77, P < 0.0005, 10 studies). The same meta-analysis also found that MDD was more common among individuals with two or more classic risk factors for vascular disease compared with those with one or no risk factors (OR 1.49, 95% CI 1.27 to 1.7, P < 0.0005, 18 studies). These findings remained robust after statistical adjustments for chronic illness and disability. Results from meta-analyses having assessed the association from the reverse direction, indicate that MDD is not only an independent risk factor for cardiovascular disease (relative risk (RR) 2.69, 95% CI 1.63 to 4.43, P < 0.001, 11 studies), but is also associated with a 3-fold increased cardiovascular disease mortality rate (OR 2.61, 95% CI 1.53 to 4.47, P = 0.0004). Related studies report similar findings.

Blood–brain barrier unit hyperpermeability

8The BBB consists of the neurovascular endothelium, extracellular matrix basal lamina, and astrocytic end-feet processes. The BBB secures the brain’s immune-privileged status by restricting the entry of peripheral inflammatory mediators (for example, cytokines, antibodies), which can impair neurotransmission. Neurovascular endothelial cells regulate influx of essential nutrients, efflux of toxic substances, ionic homeostasis of brain interstitial fluid, and prevent brain influx of peripheral neuroactive substances, neurotransmitters, and water-soluble molecules. Evidence of an association between BBB hyperpermeability and MDD derives mainly from studies having assessed cerebrospinal fluid (CSF)-to-serum ratios of various molecules, as well as evaluations concerning P-glycoprotein.

9Evidence of an elevated CSF-to-serum albumin ratio in some MDD patients is suggestive of mild hyperpermeability of blood-brain and/or blood-CSF barriers. A cross-sectional study of elderly women without dementia (11 MDD, 3 dysthymia, 70 non-depressed controls) found an elevated mean CSF-to-serum albumin ratio among those with MDD or dysthymia relative to non-depressed controls (7.1 × 10-3 vs 5.4 × 10-3, age-adjusted P < 0.015). Another study (24 affective disorders, 4,100 age-matched controls) found an increased mean CSF-to-serum albumin ratio among 37.5% of the affective disorder group (9 of 24); this value was 22% to 89% above the upper limit of healthy age-matched controls (8.7 × 10-3 vs 5.0 × 10-3). A third study (99 MDD) found that increased CSF-to-serum ratios of albumin and urate were positively associated with EEG slowing (a measure of cerebral dysfunction) and suicidality. Elevated levels of S100B protein (a marker of glial activation) and proinflammatory cytokines in the serum, CSF, and neuropathological specimens from persons with MDD may be related to increased permeability of blood-brain and blood-CSF barriers. Elevated levels of these molecules may reflect their increased synthesis and increased efflux from (a) brain parenchyma into the blood (BBB hyperpermeability), and (b) blood into the CSF (blood-CSF hyperpermeability).

10Alteration of BBB endothelial expression of P-glycoprotein (a multidrug efflux transporter) is documented in some persons with MDD. Reduced expression or function of P-glycoprotein may facilitate BBB permeability to neurotoxic substances. Positron emission tomography (PET) utilizing the [(11)C]-verapamil radioligand for P-glycoprotein in humans with MDD and in Wistar rats exhibiting depressive-like behavior showed that chronic stress exposure and administration of antidepressants inhibited and enhanced P-glycoprotein function, respectively. A human genetics study (631 MDD, 110 non-depressed controls) revealed a significant association between alteration of the P-glycoprotein encoding gene ATP-binding cassette, subfamily B member 1 (ABCB1) and MDD (P = 0.034).

Oxidative stress

11Common ROS include superoxide (O2-), hydroxyl radical (HO-), hydrogen peroxide (H2O2-), and peroxynitrite (ONOO-). ONOO- is a highly reactive oxidant generated by the reaction of nitric oxide (NO) with O2-. The brain is particularly susceptible to oxidative stress due to high levels of peroxidizable polyunsaturated fatty acids and transition minerals (reduced form) that induce lipid peroxidation and convert H2O2- to HO-; additionally, the brain’s oxygen demand is particularly high and the presence of antioxidant defense mechanisms is relatively limited.

12Although ROS can limit injury and promote recovery at low levels, ROS facilitate oxidative injury at high levels by damaging biological macromolecules, such as lipids, proteins, and DNA. We hypothesize that oxidative stress associated with MDD may impair neurovascular function through several mechanisms, with an emphasis on mechanisms that can shift the functional balance between beneficial endothelial nitric oxide synthase (eNOS)-generated NO versus harmful eNOS-generated O2- (Figure 2 and Table 1).

13NO has been termed ‘Janus faced’ owing to its ability to either protect vascular endothelial cell function in some instances, while impairing it in others. These differential effects of NO are primarily determined by its cellular source (non-endothelial vs endothelial) and concentration (high vs low). NOS isoforms regulate NO synthesis in the brain. Of these, one is constitutively expressed in endothelial cells and astrocytes (eNOS) (that is, eNOS), and another is expressed in neurons (neuronal NOS (nNOS)).

14eNOS regulates vascular smooth muscle tone and nNOS modulates neurotransmission. The expression of a third NOS isoform, iNOS, occurs in glial and inflammatory cells and is induced by pathological inflammatory states, such as following trauma. More recently, a fourth NOS isoform was described, mitochondrial (mtNOS), which is an eNOS-like isoform that is constitutively expressed in the inner mitochondrial membrane. When combined with O2-, NO produced by non-endothelial cellular sources (as regulated by nNOS, iNOS) can impair the vascular endothelium and disrupt BBB integrity. nNOS activity itself is positively regulated by Ca2+ influx, whereas iNOS activity is positively regulated by proinflammatory cytokine and NFκB signaling.

15NO produced by endothelial cells (as regulated by eNOS) increases cellular levels of cyclic guanosine monophosphate, which can increase cerebral blood flow via mechanisms involving endothelium-dependent vasodilation and platelet aggregation inhibition. In vitro studies showed that endothelial-derived NO may dilate cerebral vessels by inhibiting the synthesis of 20-hydroxyeicostetranoic acid—an arachidonic acid metabolite that promotes vasoconstriction. Endothelial-derived NO can also limit endothelial vascular oxidative stress injury by scavenging free radicals. Endothelial eNOS mediates NO synthesis via oxidative conversion of l-arginine to l-citrulline. Activity of eNOS is modulated by several factors, including endothelial levels of Ca2+, arginine (eNOS substrate), as well as tetrahydrobiopterin (BH4) (eNOS cofactor) (Figure 2). Downregulation of eNOS activity can decrease endothelial NO levels, potentially resulting in (a) reduced cerebral blood flow, (b) increased platelet aggregation, which may contribute to the increased risk of cardiovascular disease in MDD, (c) increased oxidative stress, and (d) decreased vascular reactivity.

16Under oxidative conditions, such as those associated with MDD (Figure 1), endothelial levels of BH4 are decreased due to increased oxidative conversion of BH4 to dihydrobiopterin (BH2). Decreased endothelial levels of BH4 and increased endothelial levels of BH2 (which can also reduce BH4 binding to eNOS) uncouple l-arginine oxidation from the electron transfer process and shift the eNOS substrate from l-arginine to molecular oxygen (that is, eNOS uncoupling), thereby promoting the synthesis of harmful O2- instead of beneficial NO. Once formed, O2- reacts with residual NO (still being produced at a lower rate) to form ONOO-. ONOO- in turn oxidizes BH4, thereby further decreasing its levels in a positive feedback loop (Figure 2).

17Data from in vitro animal models of neurological disorders show that upregulation of iNOS and nNOS expression and downregulation of eNOS expression can worsen neuronal injury. In murine models of ischemic stroke, knocking out iNOS and nNOS decreased the size of infarct while knocking out eNOS expanded infracted zone, compared to wild-type mice. In animal models of traumatic brain injury, increased levels of endothelial ONOO- are associated with BBB breakdown and neurobehavioral deficits; additionally, treatment with the antioxidant S-nitrosoglutathione enhances neural reparative mechanisms and improves neurovascular unit function by decreasing endothelial ONOO- synthesis.

18Clinical and experimental studies suggest that eNOS uncoupling can contribute to vascular endothelial dysfunction in both cardiovascular diseases and MDD. In cardiovascular diseases, eNOS uncoupling-mediated endothelial dysfunction is thought to result from (a) increased O2- synthesis (through an NAD(P)H oxidase-dependent mechanism), (b) increased ONOO- formation, and (c) decreased BH4 levels. In MDD, however, the potential contribution of eNOS uncoupling to vascular endothelial dysfunction is inferred from less direct evidence. For example, several clinical studies of persons with MDD have shown significant reductions in eNOS activity and NO levels in platelets and sera, respectively. In a study of 57 MDD patients randomized to either citalopram (n = 36) or placebo (n = 21), a 3-month trial of citalopram was associated with a statistically significant increase in serum NO levels compared to placebo (P = 0.005). Another study involving a 2-month trial of paroxetine reproduced similar results. Fluoxetine treatment in a chronic stress mouse model restored previously deficient aortic endothelial NO levels, suggesting that eNOS uncoupling may not only occur in MDD, but also that eNOS recoupling may be one of the mechanisms by which antidepressants exert their therapeutic effects.

19The antidepressant effect of l-methylfolate, which can reverse eNOS uncoupling in vitro via upregulating BH4 synthesis, suggests that eNOS uncoupling contributes to the neurobiology of MDD. A randomized controlled trial showed that adding l-methylfolate at 15 mg/day, but not at 7.5 mg/day, to a stable regimen of selective serotonin reuptake inhibitors (SSRIs) had superior efficacy to SSRIs plus placebo. Although the authors attributed BH4 augmenting the antidepressant effects of SSRIs to direct activation of the rate-limiting enzymes of monoamine synthesis (serotonin, norepinephrine, dopamine), we suggest that these effects may also be related to the ability of BH4 to reverse eNOS uncoupling.

20Although regionally selective (thalamic nuclei, prefrontal, anterior cingulate, temporal, and occipital cortices) cerebral hypoperfusion abnormalities in MDD have traditionally been attributed to depressed mood states and reduced neuronal activity, these findings may also be related to eNOS uncoupling (Figure 2). Sustained cerebral hypoperfusion can impair endothelial mitochondrial oxidative function, resulting in increased synthesis of endothelial ROS. ROS can in turn promote eNOS uncoupling, leading to reduced vasodilatory endothelial NO levels and cerebral hypoperfusion in a positive feedback loop. In addition, SSRIs have been shown to induce vasodilation through eNOS-mediated downregulation of NO. We recently reported a case of chronic and refractory MDD with moderately severe bifrontal cerebral hypoperfusion (seen via single photon emission tomography (SPECT)) associated with lipofuscin granule accumulation (a marker of oxidative stress) (Figure 2) identified exclusively within the neurovascular unit (predominately within the endothelium); restoration of cerebral hypoperfusion in temporal association with intravenous immunoglobulin and minocycline therapy was accompanied with significant improvement of depressive symptoms, after more than 20 years of refractoriness to conventional psychiatric treatments. We suggest that eNOS uncoupling may occur in MDD primarily as the result of non-heritable factors such as oxidative mechanisms. Indeed, several genetic studies show a non-significant association between eNOS gene polymorphisms and MDD.

21Under oxidative conditions, BBB endothelial cells are not only the source of harmful eNOS uncoupling, but also can be the target of oxidative damage. In neurological disorders associated with neurovascular dysfunction, oxidative stress can also increase BBB permeability through several mechanisms (Table 1), which include: (a) activation of metalloproteinase (MMP)-2/9 directly or indirectly through proinflammatory cytokines; (b) downregulation of endothelial expression of E-cadherin; (c) alteration of the expression, distribution, and phosphorylation of BBB tight junction proteins (for example, claudin, occluding, ZO proteins) by molecules such as phosphatidylinositol-3-kinase γ; (d) alteration of endothelial cytoskeletal structure; (e) induction of endothelial NMDAR subunit expression such as NMDA receptor subunit 1 (NR1) subunit, leading endothelial excitotoxicity; and (f) impairment of vascular endothelial mitochondrial oxidative metabolism. The relevance of these mechanisms to the neurobiology of MDD, however, remains unclear (Table 1 and Figure 2).

Neuroinflammation

22Neuroinflammation may impair neurovascular function and increase BBB permeability in MDD (Figure 2 and Table 1). Astroglial cells are an integral part of the neurovascular unit. They are involved in regulating blood flow, BBB permeability, energy metabolism, and neuronal signaling. Astroglial loss has been consistently documented in functionally relevant areas (prefrontal and cingulate cortices, amygdala, hippocampus) among persons with MDD. Other studies have documented decreased expression of the astroglial end-feet process water channel, aquaporin 4 (AQP4) in the orbitofrontal cortical gray matter (but not white matter) of individuals with MDD relative to non-depressed controls. Animal models of depressive-like behavior also found decreased AQP4 density in association with oxidative stress. Decreased AQP4 density may impair critical glial-vascular homeostatic pathways within the neurovascular unit and increase BBB permeability (Figure 2). Reduced AQP4 density may also contribute to cerebral perfusion and metabolic abnormalities detected by SPECT and PET imaging in human MDD.

23Microglia provide immune surveillance and regulate developmental synaptic pruning of the brain. Although transient microglial activation and proliferation (MAP) can limit neuronal injury and enhance recovery (beneficial phenotype), persistent MAP can induce and exacerbate neuronal injury (harmful phenotype). Harmful MAP is implicated in the pathophysiology of MDD, though neuropathological evidence of MAP in the brains of subjects with MDD is inconsistent. One neuropathological study found a positive association between suicidality and both MAP density and microglial quinolinic acid expression. In rats, chronic psychological stress promotes MAP in the prefrontal cortex, amygdala, and hippocampus. Recent meta-analysis in MDD patients confirmed elevation of serum levels of proinflammatory cytokines, such as interleukin 6 (IL-6) and TNFα. Multiple in vitro studies of various neurological conditions showed that MAP and proinflammatory cytokines could increase BBB permeability (Figures 1 and 2) (Table 1). BBB hyperpermeability may in turn increase crosstalk between innate and adaptive immunity, thereby resulting in further upregulation of MAP and brain cytokine production in a positive feedback loop. MAP can activate iNOS, increase ROS synthesis, and promote COX2 expression within the neurovascular unit; these factors may increase BBB permeability in vitro. MAP and proinflammatory cytokines can release and activate matrix metalloproteinases (MMPs), which have been shown in vitro to disrupt BBB endothelial tight junction proteins and increase BBB opening. Serum MMP-9 levels have been shown to correlate with depressive symptom severity in humans (as assessed by the Hamilton Depression Scale). Highly reproducible in vitro data showed that proinflammatory cytokines (TNFα, IL-1β, interferon γ (IFNγ)) can cause a dose-dependent increase in BBB permeability by inducing expression of intercellular adhesion molecule 1 (ICAM-1) on the luminal surface of BBB endothelial cells in animals and humans. One neuropathological study found a significant increase in the ICAM-1 expression in the deep white matter of the dorsolateral prefrontal cortex in MDD relative to controls. Another study showed SSRIs can reduce vascular endothelial expression and serum levels of both ICAM-1 and vascular cell adhesion molecule 1 (VCAM-1). Thus, increased BBB endothelial cell expression of adhesion molecules may be one mechanism by which BBB hyperpermeability occurs in MDD (Figure 2). However, contrary to this interpretation, a separate postmortem study has shown decreased expression of VCAM-1 and ICAM-1 in the orbitofrontal cortex in depressed subjects compared with non-depressed controls. Increased TNFα production occurring after acute myocardial infarction is associated with an increased risk of MDD and BBB endothelial hyperpermeability. In vitro animal studies showed that TNFα could reduce mitochondrial density and impair mitochondrial oxidative metabolism, leading to increased ROS synthesis. Several lines of human and animal evidence implicate mitochondrial abnormalities in MDD. In vitro data mechanistically link mitochondrial abnormalities to oxidative injury-related vascular abnormalities (Figures 1 and 2). Thus, proinflammatory cytokines may also induce depression and increase BBB permeability by promoting oxidative stress and impairing mitochondrial functions. The relevance of these mechanisms to MDD, however, remains unproven.

24Bradykinin is a polypeptide that mediates inflammation, vasodilation, and increased capillary permeability. Human data of bradykinin alterations in MDD are limited to evidence of functional single nucleotide polymorphisms of the bradykinin receptor B2 gene (BDKRB2) (Table 1). LPS-induced depressive-like behavior in mice was associated with upregulation of bradykinin activity and bradykinin B1 receptor expression; further, selective bradykinin B1 receptor antagonists improved depression-like behavior. Activation of bradykinin and its inducible B1 and constitutively expressed B2 receptors induces inflammation, promotes oxidative injury, and increases BBB permeability (Figures 1 and 2). Bradykinin activation can augment the astroglial NFκB pathway-mediated IL-6 production, which may increase BBB permeability. Bradykinin activation can also stimulate phospholipase A2 activity, which in turn enhances arachidonic acid release and its metabolism, leading to increased malondialdehyde and NO production that may increase BBB permeability. Activation of B2 receptor increases endothelial Ca2+ influx, which can activate pro-oxidant enzymes involved in ROS synthesis. Increased ROS production can increase BBB permeability and its susceptibility to the harmful effects of bradykinin. In vitro human studies showed that inflammation-related upregulation of BBB endothelial bradykinin B1 receptor expression could increase BBB permeability.

25Glutamatergic hyperfunction may contribute to neurovascular dysfunction in MDD (Figure 2 and Table 1). Numerous experimental paradigms such as, brain proton magnetic resonance imaging, postmortem brain investigations, and CSF studies, have documented glutamatergic hyperfunction in persons with MDD. Neuroinflammation may contribute to hyperglutamatergia in a positive feedback loop through several potential mechanisms, which include: (a) inhibition and reversal of astroglial excitatory amino acid transporter-mediated glutamate reuptake function (this process mediates more than 90% of glutamate uptake); (b) stimulation of microglial synthesis of quinolinic acid, which can promote synaptosomal glutamate release and increase astroglial glutamate and d-serine release; and (c) upregulation of MAP expression of Xc antiporter system, which increases microglial glutamate release. Postmortem investigations of N-methyl-d-aspartate receptors (NMDARs) subunit expression in the brains of MDD subjects compared with those of non-depressed controls show (a) an increase or no change of NR1 subunit expression in the hippocampus, (b) an increase of NR2A and NR2B subunit expression in the hippocampus, (c) a decrease or no change in NR1 subunit expression in the prefrontal cortex, (d) a decrease of NR2A and NR2B subunit expression in the prefrontal cortex, and (e) an increase of NR2A subunit expression in the lateral amygdalae. Binding of excess glutamate to its dysregulated BBB endothelial ionic NMDARs and metabotropic glutamate receptors (mGluRs) can increase intracellular Ca2+ level-dependent oxidative stress and BBB permeability via increasing Ca2+ influx and release from endoplasmic reticulum stores, respectively. Animal data showed that NMDAR activation facilitates free radical production such as ONOO- (Figures 1 and 2). Administration of glutamate receptor antagonists has been shown to attenuate NMDAR-induced oxidative stress. Animal studies showed that oxidative stress in turn can alter cerebral endothelial NMDAR subunit composition and upregulate NR1 subunit expression, thus setting up a positive feedback loop that increases BBB endothelium vulnerability to both glutamate excitotoxicity and oxidative stress. Alteration of endothelial NMDAR subunit compositions may also reduce cerebral blood flow, as physiologic activation of endothelial NMDAR may activate eNOS and increase endothelial-derived NO. BBB breakdown may also increase CNS glutamate levels via disruption of endothelial-bound glutamate efflux transporters; in turn, hyperglutamatergia may heighten BBB susceptibility to the harmful effects of bradykinin. Administration of glutamate receptor antagonists can block bradykinin-induced endothelial Ca2+ rise. Thus, BBB hyperpermeability, increased endothelial NMDAR expression, and increased CNS glutamate levels may contribution to neuronal dysfunction in MDD.

26Mast cells are tissue-bound granulated cells most commonly found in the skin and gastrointestinal tract. They, like basophils, contain high levels of histamine and heparin. In the brain, mast cells are particularly abundant in the hypothalamic region. Mast cell activation has been associated with MDD (Table 1). Approximately 40% to 70% of persons with mastocytosis, an uncommon and heterogeneous syndrome characterized by increased mast cell density, exhibit depressive symptoms. Increased corticotropin-releasing hormone (CRH) secretion may contribute to mast cell activation associated with MDD. Experimental evidence suggests that mast cells can cause inflammation, modulate BBB permeability, and facilitate NMDAR-induced neuronal excitotoxicity (Figure 2). Mast cell activation can release inflammatory substances (for example, IL-6, TNFα, vascular endothelial growth factor) and stimulate vascular endothelial cell adhesion molecule expression. These molecules can disrupt BBB integrity and enhance inflammatory cell transmigration into the brain.

Future Directions

27Human and animal studies are needed to evaluate the validity of the BBB dysfunction hypothesis and to explore the mechanistic links between oxidative stress, eNOS uncoupling, and neuroinflammation and neurovascular unit dysfunction with BBB hyperpermeability in MDD. Future postmortem studies investigating the relationship between neurovascular unit dysfunction with BBB hyperpermeability and MDD should focus primarily on the neuroanatomical regions where astroglial loss and MAP have been documented in MDD brains such as anterior mid/cingulate cortex, prefrontal cortex, amygdala, and white matter. Developing methods with increased sensitivity to detect and quantitate subtle BBB hyperpermeability in MDD are likely to be informative. These methods might utilize fluorescent dyes in animal models of depressive-like behavior similar to those developed for in vivo imaging of specific neurovascular elements in animal models of various neurological disorders associated with neurovascular dysfunction: sulforhodamine 101 dye, Ca2+ sensitive dyes, glial fibrillary acidic protein (GFAP), AQP4 (astroglia), CX3C chemokine receptor 1 (CX3CR1) (microglia), dextran-conjugated dyes, alpha SMA-RFPcherry (pericytes), dextran dyes, Tie2 (vasculature) and Thy1 (neurons). A promising neuroimaging modality for visualizing MAP in humans with psychiatric illnesses is PET imaging utilizing microglial peripheral benzodiazepine receptor (also known as translocator protein) C11-PK11195 radioligand. We suspect that various neurovascular processes particularly those promoting endothelial (and potentially astroglial) eNOS dysfunction may emerge as key targets for cellular and molecular research in MDD. Adequately powered randomized controlled trials investigating the effects of anti-inflammatory agents and antioxidants in MDD should also assess their effects on cerebral microvascular endothelial functions (for example, by utilizing techniques that measure peripheral vascular dilatory response and cerebral perfusion), as well as the relationship between the extent of endothelial dysfunction and the severity of depressive symptoms.

Conclusions

28Neurovascular dysfunction with BBB hyperpermeability may occur in MDD. Cumulative clinical and experimental evidence implicates oxidative stress, eNOS uncoupling, and reduced endothelial NO levels in the pathophysiology of peripheral vascular endothelial dysfunction associated with MDD. Our theoretical integration of the human and animal data links oxidative stress, eNOS uncoupling, low endothelial NO levels, and neuroinflammation to putative neurovascular and BBB abnormalities in MDD. If future studies confirm their relevance to the pathophysiology of MDD, novel agents correcting these abnormalities may prove to be effective treatment strategies.

Abbreviations

29AQP4: Aquaporin 4; BH2: Dihydrobiopterin; BH4: Tetrahydrobiopterin; CBF: Cerebral blood flow; COX2: Cyclooxygenase 2; CRH: Corticotropin-releasing hormone; CSF: Cerebrospinal fluid; CT: Computed tomography; EEG: Electroencephalogram; eNOS: Endothelial nitric oxide synthase; EAAT: Excitatory amino acid transporter; Fc: Immunoglobulin constant region; H2O2: Hydrogen peroxide; HO-: Hydroxyl radical; ICAM-1: Intercellular adhesion molecule 1; IL: Interleukin; iNOS: Inducible nitric oxide synthase; MAP: Microglial activation and proliferation; MDD: Major depressive disorder; MRI: Magnetic resonance imaging; mGluR: Metabotropic glutamate receptor; MMPs: Matrix metalloproteinases; NAD(P)H: Nicotinamide adenosine dinucleotide phosphate; Na+/K+ ATPase: Sodium-potassium adenosine triphosphates; NFκB: Nuclear factor κB; NMDAR: N-methyl-D-aspartate receptor; NO: Nitric oxide; ONOO-: Peroxynitrite; O2-: Superoxide; PET: Positron emission tomography; PLA2: Phospholipase A2; RNS: Reactive nitrogen species; ROS: Reactive oxygen species; RUR: Relative uptake ratio; SOD-1: Superoxide dismutase 1; SPECT: Single photon emission computed tomography; SSRI: Selective serotonin reuptake inhibitor; Th: T helper; TNFα: Tumor necrosis factor α; TReg: CD4+CD25+FOXP3+ T regulatory; VCAM-1: Vascular cell adhesion molecule 1.

Competing interests

30The authors declare that they have no competing interests.

Authors’ contributions

31SN, DMP conceived and designed the research; SN, DMP wrote the manuscript; SN, DMP, AN, OD, DZ, revised the manuscript for important content; SN, DMP, AN, OD, DZ, performed literature searches and gathered data for the review; all authors read and approved the final version of the manuscript for submission.

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Maes M Ruckoanich P Chang YS Mahanonda N Berk M Multiple aberrations in shared inflammatory and oxidative & nitrosative stress (IO&NS) pathways explain the co-association of depression and cardiovascular disorder (CVD), and the increased risk for CVD and due mortality in depressed patientsProg Neuropsychopharmacol Biol Psychiatry2011 35769783
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Gibson SA Korade Z Shelton RC Oxidative stress and glutathione response in tissue cultures from persons with major depressionJ Psychiatr Res2012 4613261332
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Maes M Galecki P Chang YS Berk M A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illnessProg Neuropsychopharmacol Biol Psychiatry2011 35676692
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Gawryluk JW Wang JF Andreazza AC Shao L Young LT Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disordersInt J Neuropsychopharmacol2011 14123130
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Steiner J Bogerts B Sarnyai Z Walter M Gos T Bernstein HG Myint AM Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: potential role of glial NMDA receptor modulators and impaired blood–brain barrier integrityWorld J Biol Psychiatry2012 7482492
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Microglial Dysregulation in Psychiatric Disease · 2013
No notice
20.
Gosselin RD Gibney S O'Malley D Dinan TG Cryan JF Region specific decrease in glial fibrillary acidic protein immunoreactivity in the brain of a rat model of depressionNeuroscience2009 159915925
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Banasr M Duman RS Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviorsBiol Psychiatry2008 64863870
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Haroon E Raison CL Miller AH Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behaviorNeuropsychopharmacology2012 37137162
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Cristante E McArthur S Mauro C Maggioli E Romero IA Wylezinska-Arridge M Couraud PO Lopez-Tremoleda J Christian HC Weksler BB Malaspina A Solito E Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implicationsProc Natl Acad Sci U S A2013 110832841
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Jin R Song Z Yu S Piazza A Nanda A Penninger JM Granger DN Li G Phosphatidylinositol-3-kinase gamma plays a central role in blood–brain barrier dysfunction in acute experimental strokeStroke2011 4220332044
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Van der Kooy K van Hout H Marwijk H Marten H Stehouwer C Beekman A Depression and the risk for cardiovascular diseases: systematic review and meta analysisInt J Geriatr Psychiatry2007 22613626
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54.
Chen CA Wang TY Varadharaj S Reyes LA Hemann C Talukder MA Chen YR Druhan LJ Zweier JL S-glutathionylation uncouples eNOS and regulates its cellular and vascular functionNature2010 46811151118
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Chen W Druhan LJ Chen CA Hemann C Chen YR Berka V Tsai AL Zweier JL Peroxynitrite induces destruction of the tetrahydrobiopterin and heme in endothelial nitric oxide synthase: transition from reversible to irreversible enzyme inhibitionBiochemistry2010 4931293137
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Luiking YC Ten Have GA Wolfe RR Deutz NE Arginine de novo and nitric oxide production in disease statesAm J Physiol Endocrinol Metab2012 303E1177E1189
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Ikenouchi-Sugita A Yoshimura R Hori H Umene-Nakano W Ueda N Nakamura J Effects of antidepressants on plasma metabolites of nitric oxide in major depressive disorder: comparison between milnacipran and paroxetineProg Neuropsychopharmacol Biol Psychiatry2009 3314511453
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58.
van Zyl LT Lesperance F Frasure-Smith N Malinin AI Atar D Laliberte MA Serebruany VL Platelet and endothelial activity in comorbid major depression and coronary artery disease patients treated with citalopram: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy Trial (CREATE) biomarker sub-studyJ Thromb Thrombolysis2009 274856
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Lara N Archer SL Baker GB Le Melledo JM Paroxetine-induced increase in metabolic end products of nitric oxideJ Clin Psychopharmacol2003 23408412
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Isingrini E Belzung C Freslon JL Machet MC Camus V Fluoxetine effect on aortic nitric oxide-dependent vasorelaxation in the unpredictable chronic mild stress model of depression in micePsychosom Med2012 746372
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61.
Jeynes B Provias J Significant negative correlations between capillary expressed eNOS and Alzheimer lesion burdenNeurosci Lett2009 463244248
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62.
Szolnoki Z Havasi V Bene J Komlósi K Szöke D Somogyvári F Kondacs A Szabó M Fodor L Bodor A Gáti I Wittman I Melegh B Endothelial nitric oxide synthase gene interactions and the risk of ischaemic strokeActa Neurol Scand2005 1112933
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63.
Chrissobolis S Miller AA Drummond GR Kemp-Harper BK Sobey CG Oxidative stress and endothelial dysfunction in cerebrovascular diseaseFront Biosci (Landmark Ed)2011 1617331745
Not in our library10.2741/3816
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Michel TM Pulschen D Thome J The role of oxidative stress in depressive disordersCurr Pharm Des2012 1858905899
Not in our library10.2174/138161212803523554
65.
Tobe EH Mitochondrial dysfunction, oxidative stress, and major depressive disorderNeuropsychiatr Dis Treat2013 9567573
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Frank MG Hendricks SE Bessette D Johnson DR Wieseler Frank JL Burke WJ Levels of monocyte reactive oxygen species are associated with reduced natural killer cell activity in major depressive disorderNeuropsychobiology2001 4416
Not in our library10.1159/000054906
67.
Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings · 2011
No notice
68.
Szuster-Ciesielska A Slotwinska M Stachura A Marmurowska-Michalowska H Dubas-Slemp H Bojarska-Junak A Kandefer-Szerszen M Accelerated apoptosis of blood leukocytes and oxidative stress in blood of patients with major depressionProg Neuropsychopharmacol Biol Psychiatry2008 32686694
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Shungu DC Weidschat N Mao X Pillemer S Murrough JW Mathew SJ In vivo neuroimaging evidence of oxidative stress in major depressive disorderEur Psychiatry2012 27122153731
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Shelton RC Gibson SA Korade Z Elevation of oxidative stress in tissue cultures from persons with major depressionNeuropsychopharmacology2011 36S443S444
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Selek S Dalkilic A Kaya MC Savas HA Bez Y Celik H Erel O Kaptanoglu B Herken H The relationship of oxidative metabolism to treatment response in major depression: a biological basis for treatment durationNeurol Psychiatry Brain Res2012 181518
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Sarandol A Sarandol E Eker SS Erdinc S Vatansever E Kirli S Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative - Antioxidative systemsHum Psychopharmacol2007 226773
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Rawdin BJ Mellon SH Dhabhar FS Epel ES Puterman E Su Y Burke HM Reus VI Rosser R Hamilton SP Nelson JC Wolkowitz OM Dysregulated relationship of inflammation and oxidative stress in major depressionBrain Behav Immun2013 31143152
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Rawdin B Mellon S Dhabhar F Epel E Su Y Rosser R Burke H Reus V Hamilton S Nelson C Wolkowitz O Inflammatory and oxidative stress are highly correlated in unmedicated major depressionBrain Behav Immun2012 26S47
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75.
Pasco JA Nicholson GC Ng F Henry MJ Williams LJ Kotowicz MA Hodge JM Dodd S Kapczinski F Gama CS Berk M Oxidative stress may be a common mechanism linking major depression and osteoporosisActa Neuropsychiatrica2008 20112116
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Nunes SOV Vargas HO Prado E Barbosa DS de Melo LP Moylan S Dodd S Berk M The shared role of oxidative stress and inflammation in major depressive disorder and nicotine dependenceNeurosci Biobehav Rev2013 3713361345
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77.
Mathew S Murrough J Mao X Pillemer S Shungu D Proton magnetic resonance spectroscopy measurement of brain glutathione supports increased oxidative stress in major depressive disorderNeuropsychopharmacology2010 35S151
Not in our library
78.
Maes M Mihaylova I Kubera M Uytterhoeven M Vrydags N Bosmans E Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis/chronic fatigue syndromeNeuroendocrinol Lett2009 30715722
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Leonard B Maes M Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depressionNeurosci Biobehav Rev2012 36764785
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Kotan VO Sarandol E Kirhan E Ozkaya G Kirli S Effects of long-term antidepressant treatment on oxidative status in major depressive disorder: a 24-week follow-up studyProg Neuropsychopharmacol Biol Psychiatry2011 3512841290
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Khanzode SD Dakhale GN Khanzode SS Saoji A Palasodkar R Oxidative damage and major depression: the potential antioxidant action of selective serotonin-re-uptake inhibitorsRedox Rep2003 8365370
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Herken H Gurel A Selek S Armutcu F Ozen ME Bulut M Kap O Yumru M Savas HA Akyol O Adenosine deaminase, nitric oxide, superoxide dismutase, and xanthine oxidase in patients with major depression: impact of antidepressant treatmentArch Med Res2007 38247252
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83.
Ghodake SR Suryakar AN Kulhalli PM Padalkar RK Shaikh AK A study of oxidative stress and influence of antioxidant vitamins supplementation in patients with major depressionCurr Neurobiol2012 3107111
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85.
Zafir A Ara A Banu N Invivo antioxidant status: a putative target of antidepressant actionProg Neuropsychopharmacol Biol Psychiatry2009 33220228
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86.
Brea D Roquer J Serena J Segura T Castillo J Artico S Oxidative stress markers are associated to vascular recurrence in non-cardioembolic stroke patients non-treated with statinsBMC Neurol2012 1265
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Orosz A Jann K Federspiel A Horn H Hofle O Dierks T Wiest R Strik W Muller T Walther S Reduced cerebral blood flow within the default-mode network and within total gray matter in major depressionBrain Connect2012 2303310
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Smith DJ Cavanagh JT The use of single photon emission computed tomography in depressive disordersNucl Med Commun2005 26197203
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Vlassenko A Sheline YI Fischer K Mintun MA Cerebral perfusion response to successful treatment of depression with different serotoninergic agentsJ Neuropsychiatry Clin Neurosci2004 16360363
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Najjar S Pearlman D Hirsch S Friedman K Strange J Reidy J Khoukaz M Ferrell R Devinsky O Najjar A Zagzag D Brain biopsy findings link major depressive disorder to neuroinflammation, oxidative stress, and neurovascular dysfunction: a case reportBiol Psychiatry2013 doi: 10.1016/j.biopsych.2013.07.041. [Epub ahead of print]
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Nagafusa Y Okamoto N Sakamoto K Yamashita F Kawaguchi A Higuchi T Matsuda H Assessment of cerebral blood flow findings using 99mTc-ECD single-photon emission computed tomography in patients diagnosed with major depressive disorderJ Affect Disord2012 140296299
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Johnson NA Jahng GH Weiner MW Miller BL Chui HC Jagust WJ Gorno-Tempini ML Schuff N Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experienceRadiology2005 234851859
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Ruitenberg A den Heijer T Bakker SL van Swieten JC Koudstaal PJ Hofman A Breteler MM Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam StudyAnn Neurol2005 57789794
Not in our library10.1002/ana.20493
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de la Torre JC Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesisNeurobiol Aging2000 21331342
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Waldemar G Bruhn P Kristensen M Johnsen A Paulson OB Lassen NA Heterogeneity of neocortical cerebral blood flow deficits in dementia of the Alzheimer type: a [99mTc]-d, l-HMPAO SPECT studyJ Neurol Neurosurg Psychiatry1994 57285295
Not in our library10.1136/jnnp.57.3.285
96.
Catafau AM Brain SPECT in clinical practicePart I: perfusion. J Nucl Med2001 42259271
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97.
Decreased Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF), but Not Its Precursor proBDNF, in Patients with Major Depressive Disorder · 2012
Corrected
98.
Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease · 2011
No notice
99.
Kurzepa J Bielewicz J Grabarska A Stelmasiak Z Stryjecka-Zimmer M Bartosik-Psujek H Matrix metalloproteinase-9 contributes to the increase of tau protein in serum during acute ischemic strokeJ Clin Neurosci2010 17997999
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100.
Variants of the <it>Matrix Metalloproteinase-2 </it>but not the <it>Matrix Metalloproteinase-9 </it>genes significantly influence functional outcome after stroke · 2010
Not checked
101.
Ramos-Fernandez M Bellolio MF Stead LG Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic reviewJ Stroke Cerebrovasc Dis2011 204754
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Agiostratidou G Muros RM Shioi J Marambaud P Robakis NK The cytoplasmic sequence of E-cadherin promotes non-amyloidogenic degradation of A beta precursorsJ Neurochem2006 9611821188
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Haorah J Knipe B Leibhart J Ghorpade A Persidsky Y Alcohol-induced oxidative stress in brain endothelial cells causes blood–brain barrier dysfunctionJ Leukoc Biol2005 7812231232
Not in our library10.1189/jlb.0605340
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Lochhead JJ McCaffrey G Quigley CE Finch J DeMarco KM Nametz N Davis TP Oxidative stress increases blood–brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenationJ Cereb Blood Flow Metab2010 3016251636
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105.
Matsuzaki M Takahashi R Nakayama T Shishikura K Suzuki H Hirayama Y Osawa M Oda H Disruption of endothelial tight junctions in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)Neuropediatrics2010 417274
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Kirk J Plumb J Mirakhur M McQuaid S Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood–brain barrier leakage and active demyelinationJ Pathol2003 201319327
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Oh DH Park SC Park YC Kim SH Excessive activation of the loop between the NR2B subunit of the N-methyl-D-aspartate receptor and glycogen synthase kinase-3beta in the hippocampi of patients with major depressive disorderActa Neuropsychiatrica2012 242633
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108.
Oh D Kim SH Park YC The biological pathway underlying dysregulation of hippocampal 5HT1A-NR2BGSK-3beta function in major depressionEur Neuropsychopharmacol2010 20S356
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Toro C Deakin JF NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorderSchizophr Res2005 80323330
Not in our library10.1016/j.schres.2005.07.003
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Feyissa AM Chandran A Stockmeier CA Karolewicz B Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depressionProg Neuropsychopharmacol Biol Psychiatry2009 337075
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Beneyto M Meador-Woodruff JH Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorderNeuropsychopharmacology2008 3321752186
Not in our library10.1038/sj.npp.1301604
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Neuhaus W Freidl M Szkokan P Berger M Wirth M Winkler J Gabor F Pifl C Noe CR Effects of NMDA receptor modulators on a blood–brain barrier in vitro modelBrain Res2011 13944961
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Moreno J Gaspar E Lopez-Bello G Juarez E Alcazar-Leyva S Gonzalez-Trujano E Pavon L Alvarado-Vasquez N Increase in nitric oxide levels and mitochondrial membrane potential in platelets of untreated patients with major depressionPsychiatry Res2013 209447452
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Gardner A Pagani M Wibom R Nennesmo I Jacobsson H Hallstom T Alterations of rCBF and mitochondrial dysfunction in major depressive disorder: a case reportActa Psychiatr Scand2003 107233238
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Mitochondrial Variants in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder · 2009
No notice
116.
McPhie DL Logan D Sargent L Berry JT Ravichandran C Carpenter A Cohen B Detecting disease-specific differences in mitochondrial morphology and distribution in fibroblasts from patients with bipolar, schizophrenic, and major depressive disordersNeuropsychopharmacology2012 38S287
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Koene S Kozicz TL Rodenburg RJT Verhaak CM de Vries MC Wortmann S van de Heuvel L Smeitink JAM Morava E Major depression in adolescent children consecutively diagnosed with mitochondrial disorderJ Affect Disord2009 114327332
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Gardner A Johansson A Wibom R Nennesmo I Von Dobeln U Hagenfeldt L Hallstrom T Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patientsJ Affect Disord2003 765568
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Gardner A Boles RG Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disordersProg Neuropsychopharmacol Biol Psychiatry2011 35730743
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120.
Neuroanatomical Pattern of Mitochondrial Complex I Pathology Varies between Schizophrenia, Bipolar Disorder and Major Depression · 2008
No notice
121.
Abdallah CG Mason GF De Feyter H Fasula M Kelmendi B Simen A Jiang L Krystal JH Rothman DL Sanacora G Reduced mitochondrial energy production in major depressive disorder: associations with the serotonin transporter and glutamine synthetase genesNeuropsychopharmacology2012 38S127S128
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Della FP Abelaira HM Réus GZ Antunes AR Dos Santos MA Zappelinni G Steckert AV Vuolo F Galant LS Dal-Pizzol F Kapczinski F Quevedo J Tianeptine exerts neuroprotective effects in the brain tissue of rats exposed to the chronic stress modelPharmacol Biochem Behav2012 103395402
Not in our library10.1016/j.pbb.2012.09.018
123.
Triggers and Effectors of Oxidative Stress at Blood-Brain Barrier Level: Relevance for Brain Ageing and Neurodegeneration · 2013
No notice
124.
Kimura A Sakurai T Yamada M Koumura A Hayashi Y Tanaka Y Hozumi I Ohtaki H Chousa M Takemura M Seishima M Inuzuka T Antibodies against the tom40 subunit of the translocase of the outer mitochondrial membrane complex and cognitive impairment in Alzheimer's diseaseJ Alzheimers Dis2012 29373377
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Mecocci P MacGarvey U Beal MF Oxidative damage to mitochondrial DNA is increased in Alzheimer's diseaseAnn Neurol1994 36747751
Not in our library10.1002/ana.410360510
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Miguel-Hidalgo JJ Baucom C Dilley G Overholser JC Meltzer HY Stockmeier CA Rajkowska G Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorderBiol Psychiatry2000 48861873
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Altshuler LL Abulseoud OA Foland Ross L Bartzokis G Chang S Mintz J Hellemann G Vinters HV Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorderBipolar Disord2010 12541549
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Webster MJ Knable MB Johnston-Wilson N Nagata K Inagaki M Yolken RH Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depressionBrain Behav Immun2001 15388400
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Doyle C Deakin JFW Fewer astrocytes in frontal cortex in schizophrenia, depression and bipolar disorderSchizophr Res2002 53106
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Johnston-Wilson NL Sims CD Hofmann JP Anderson L Shore AD Torrey EF Yolken RH Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology ConsortiumMol Psychiatry2000 5142149
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Tseng PT Lee Y Lin PY Age-associated decrease in serum glial cell line-derived neurotrophic factor levels in patients with major depressive disorderProg Neuropsychopharmacol Biol Psychiatry2013 40334339
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132.
Ordway GA Szebeni A Chandley MJ Stockmeier CA Xiang L Newton SS Turecki G Duffourc MM Zhu MY Zhu H Szebeni K Low gene expression of bone morphogenetic protein 7 in brainstem astrocytes in major depressionInt J Neuropsychopharmacol2012 15855868
Not in our library10.1017/s1461145711001350
133.
Diniz BS Teixeira AL Miranda AS Talib LL Gattaz WF Forlenza OV Circulating Glial-derived neurotrophic factor is reduced in late-life depressionJ Psychiatr Res2012 46135139
Not in our library10.1016/j.jpsychires.2011.09.007
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Li B Dong L Wang B Cai L Jiang N Peng L Cell type-specific gene expression and editing responses to chronic fluoxetine treatment in the in vivo mouse brain and their relevance for stress-induced anhedoniaNeurochem Res2012 3724802495
Not in our library10.1007/s11064-012-0814-1
135.
Araya-Callis C Hiemke C Abumaria N Flugge G Chronic psychosocial stress and citalopram modulate the expression of the glial proteins GFAP and NDRG2 in the hippocampusPsychopharmacology (Berl)2012 224209222
Not in our library10.1007/s00213-012-2741-x
136.
Sun JD Liu Y Yuan YH Li J Chen NH Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in ratsNeuropsychopharmacology2012 3713051320
Not in our library10.1038/npp.2011.319
137.
Allaman I Fiumelli H Magistretti PJ Martin JL Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytesPsychopharmacology (Berl)2011 2167584
Not in our library10.1007/s00213-011-2190-y
138.
Ye Y Wang G Wang H Wang X Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depressionNeurosci Lett2011 5031519
Not in our library10.1016/j.neulet.2011.07.055
139.
Hayakawa K Pham LD Katusic ZS Arai K Lo EH Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recoveryProc Natl Acad Sci USA2012 10975057510
Not in our library10.1073/pnas.1121146109
140.
Heinemann U Kaufer D Friedman A Blood–brain barrier dysfunction, TGFbeta signaling, and astrocyte dysfunction in epilepsyGlia2012 6012511257
Not in our library10.1002/glia.22311
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Merlini M Meyer EP Ulmann-Schuler A Nitsch RM Vascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta miceActa Neuropathol2011 122293311
Not in our library10.1007/s00401-011-0834-y
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Rajkowska G Hughes J Stockmeier CA Javier Miguel-Hidalgo J Maciag D Coverage of blood vessels by astrocytic endfeet is reduced in major depressive disorderBiol Psychiatry2013 73613621
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143.
Liu L Lu Y Kong H Li L Marshall C Xiao M Ding J Gao J Hu G Aquaporin-4 deficiency exacerbates brain oxidative damage and memory deficits induced by long-term ovarian hormone deprivation and d-galactose injectionInt J Neuropsychopharmacol2012 15568
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Takahashi T Fujihara K Nakashima I Misu T Miyazawa I Nakamura M Watanabe S Ishii N Itoyama Y Establishment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis opticaTohoku J Exp Med2006 210307313
Not in our library10.1620/tjem.210.307
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Takahashi T Fujihara K Nakashima I Misu T Miyazawa I Nakamura M Watanabe S Shiga Y Kanaoka C Fujimori J Sato S Itoyama Y Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titreBrain2007 13012351243
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Tanaka K Tani T Tanaka M Saida T Idezuka J Yamazaki M Tsujita M Nakada T Sakimura K Nishizawa M Anti-aquaporin 4 antibody in selected Japanese multiple sclerosis patients with long spinal cord lesionsMult Scler2007 13850855
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147.
Müller N Schwarz MJ The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depressionMol Psychiatry2007 129881000
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148.
Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission? · 2011
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149.
Fenn AM Henry CJ Huang Y Dugan A Godbout JP Lipopolysaccharide-induced interleukin (IL)-4 receptor-alpha expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged miceBrain Behav Immun2012 26766777
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Henry CJ Huang Y Wynne AM Godbout JP Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokinesBrain Behav Immun2009 23309317
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Wang Y Lawson MA Dantzer R Kelley KW LPS-induced indoleamine 2,3-dioxygenase is regulated in an interferon-gamma-independent manner by a JNK signaling pathway in primary murine microgliaBrain Behav Immun2010 24201209
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Zhang F Zhou H Wilson BC Shi JS Hong JS Gao HM Fluoxetine protects neurons against microglial activation-mediated neurotoxicityParkinsonism Relat Disord2012 18Suppl 1S213S217
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Najjar S Pearlman D Miller DC Devinsky O Refractory epilepsy associated with microglial activationNeurologist2011 17249254
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Devinsky O Vezzani A Najjar S De Lanerolle NC Rogawski MA Glia and epilepsy: excitability and inflammationTrends Neurosci2013 36174184
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Janelidze S Mattei D Westrin A Traskman-Bendz L Brundin L Cytokine levels in the blood may distinguish suicide attempters from depressed patientsBrain Behav Immun2011 25335339
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Dantzer R O'Connor JC Freund GG Johnson RW Kelley KW From inflammation to sickness and depression: when the immune system subjugates the brainNat Rev Neurosci2008 94656
Not in our library10.1038/nrn2297
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O'Connor JC Lawson MA Andre C Moreau M Lestage J Castanon N Kelley KW Dantzer R Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in miceMol Psychiatry2009 14511522
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Gratacòs M Costas J de Cid R Bayés M González JR Baca-García E de Diego Y Fernández-Aranda F Fernández-Piqueras J Guitart M Martín-Santos R Martorell L Menchón JM Roca M Sáiz-Ruiz J Sanjuán J Torrens M Urretavizcaya M Valero J Vilella E Estivill X Carracedo A Psychiatric Genetics Network GroupIdentification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopmentAm J Med Genet Neuropsychiatr Genet2009 150808816
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Viana AF Maciel IS Dornelles FN Figueiredo CP Siqueira JM Campos MM Calixto JB Kinin B1 receptors mediate depression-like behavior response in stressed mice treated with systemic E. coli lipopolysaccharideJ Neuroinflammation2010 798
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Hashimoto K Sawa A Iyo M Increased levels of glutamate in brains from patients with mood disordersBiol Psychiatry2007 6213101316
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Sanacora G Gueorguieva R Epperson CN Wu YT Appel M Rothman DL Krystal JH Mason GF Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depressionArch Gen Psychiatry2004 61705713
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Eid T Thomas MJ Spencer DD Runden-Pran E Lai JC Malthankar GV Kim JH Danbolt NC Ottersen OP de Lanerolle NC Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsyLancet2004 3632837
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Mathern GW Mendoza D Lozada A Pretorius JK Dehnes Y Danbolt NC Nelson N Leite JP Chimelli L Born DE Sakamoto AC Assirati JA Fried I Peacock WJ Ojemann GA Adelson PD Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsyNeurology1999 52453472
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Shalev H Serlin Y Friedman A Breaching the blood–brain barrier as a gate to psychiatric disorderCardiovasc Psychiatry Neurol2009 2009278531
Not in our library10.1155/2009/278531
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Piche T Saint-Paul MC Dainese R Marine-Barjoan E Iannelli A Montoya ML Peyron JF Czerucka D Cherikh F Filippi J Tran A Hébuterne X Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndromeGut2008 57468473
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Neuro-inflammation, blood-brain barrier, seizures and autism · 2011
Not checked
171.
Theoharides TC Konstantinidou AD Corticotropin-releasing hormone and the blood–brain-barrierFront Biosci2007 1216151628
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Lekakis J Ikonomidis I Papoutsi Z Moutsatsou P Nikolaou M Parissis J Kremastinos DT Selective serotonin re-uptake inhibitors decrease the cytokine-induced endothelial adhesion molecule expression, the endothelial adhesiveness to monocytes and the circulating levels of vascular adhesion moleculesInt J Cardiol2010 139150158
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Miguel-Hidalgo JJ Overholser JC Jurjus GJ Meltzer HY Dieter L Konick L Stockmeier CA Rajkowska G Vascular and extravascular immunoreactivity for intercellular adhesion molecule 1 in the orbitofrontal cortex of subjects with major depression: age-dependent changesJ Affect Disord2011 132422431
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Hwang SJ Ballantyne CM Sharrett AR Smith LC Davis CE Gotto AM Jr Boerwinkle E Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) studyCirculation1997 9642194225
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de Klerk OL Bosker FJ Willemsen AT Van Waarde A Visser AK de Jager T Dagyte G den Boer JA Dierckx RA Meerlo P Chronic stress and antidepressant treatment have opposite effects on P-glycoprotein at the blood–brain barrier: an experimental PET study in ratsJ Psychopharmacol2010 2412371242
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Serlin Y Levy J Shalev H Vascular pathology and blood–brain barrier disruption in cognitive and psychiatric complications of type 2 diabetes mellitusCardiovasc Psychiatry Neurol2011 2011609202
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Abbott NJ Ronnback L Hansson E Astrocyte-endothelial interactions at the blood–brain barrierNat Rev Neurosci2006 74153
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Bechter K Reiber H Herzog S Fuchs D Tumani H Maxeiner HG Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunctionJ Psychiatr Res2010 44321330
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Serum S100B: a potential biomarker for suicidality in adolescents? · 2010
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Miller BJ Buckley P Seabolt W Mellor A Kirkpatrick B Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effectsBiol Psychiatry2011 70663671
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Hawkins BT Sykes DB Miller DS Rapid, reversible modulation of blood–brain barrier P-glycoprotein transport activity by vascular endothelial growth factorJ Neurosci2010 3014171425
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Förstermann U Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversalBiol Chem2006 38715211533
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Chuang YC Mitochondrial dysfunction and oxidative stress in seizure-induced neuronal cell deathActa Neurol Taiwan2010 19315
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Joynt KE Whellan DJ O'Connor CM Depression and cardiovascular disease: mechanisms of interactionBiol Psychiatry2003 54248261
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Sun CW Falck JR Okamoto H Harder DR Roman RJ Role of cGMP versus 20-HETE in the vasodilator response to nitric oxide in rat cerebral arteriesAm J Physiol Heart Circ Physiol2000 279H339H350
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Attwell D Buchan AM Charpak S Lauritzen M Macvicar BA Newman EA Glial and neuronal control of brain blood flowNature2010 468232243
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Liu VW Huang PL Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted miceCardiovasc Res2008 771929
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Szabo C Ischiropoulos H Radi R Peroxynitrite: biochemistry, pathophysiology and development of therapeuticsNat Rev Drug Discov2007 6662680
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Chrapko W Jurasz P Radomski MW Archer SL Newman SC Baker G Lara N Le Melledo JM Alteration of decreased plasma NO metabolites and platelet NO synthase activity by paroxetine in depressed patientsNeuropsychopharmacology2006 3112861293
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Chrapko WE Jurasz P Radomski MW Lara N Archer SL Le Melledo JM Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorderBiol Psychiatry2004 56129134
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Khan M Sakakima H Dhammu TS Shunmugavel A Im YB Gilg AG Singh AK Singh I S-nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in ratsJ Neuroinflammation2011 878
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Not in our library10.1523/jneurosci.17-23-09157.1997
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Huang Z Huang PL Ma J Meng W Ayata C Fishman MC Moskowitz MA Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-l-arginineJ Cereb Blood Flow Metab1996 16981987
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Shimizu-Sasamata M Bosque-Hamilton P Huang PL Moskowitz MA Lo EH Attenuated neurotransmitter release and spreading depression-like depolarizations after focal ischemia in mutant mice with disrupted type I nitric oxide synthase geneJ Neurosci1998 1895649571
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Lu Q Xia N Xu H Guo L Wenzel P Daiber A Munzel T Forstermann U Li H Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stressNitric Oxide2011 24132138
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Masano T Kawashima S Toh R Satomi-Kobayashi S Shinohara M Takaya T Sasaki N Takeda M Tawa H Yamashita T Yokoyama M Hirata K Beneficial effects of exogenous tetrahydrobiopterin on left ventricular remodeling after myocardial infarction in rats: the possible role of oxidative stress caused by uncoupled endothelial nitric oxide synthaseCirc J2008 7215121519
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Papakostas GI Shelton RC Zajecka JM Etemad B Rickels K Clain A Baer L Dalton ED Sacco GR Schoenfeld D Pencina M Meisner A Bottiglieri T Nelson E Mischoulon D Alpert JE Barbee JG Zisook S Fava M l-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trialsAm J Psychiatry2012 16912671274
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Srivastava K Bath PMW Bayraktutan U Current therapeutic strategies to mitigate the eNOS dysfunction in ischaemic strokeCell Mol Neurobiol2012 32319336
Not in our library10.1007/s10571-011-9777-z
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Aliev G Obrenovich ME Tabrez S Jabir NR Reddy VP Li Y Burnstock G Cacabelos R Kamal MA Link between cancer and alzheimer disease via oxidative stress induced by nitric oxide-dependent mitochondrial DNA overproliferation and deletionOxid Med Cell Longev2013 2013962984
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Aliev G Palacios HH Walrafen B Lipsitt AE Obrenovich ME Morales L Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer diseaseInt J Biochem Cell Biol2009 4119892004
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Aliev G Seyidova D Lamb BT Obrenovich ME Siedlak SL Vinters HV Friedland RP LaManna JC Smith MA Perry G Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic miceNeurol Res2003 25665674
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Gray DA Woulfe J Lipofuscin and aging: a matter of toxic wasteSci Aging Knowledge Environ2005 2005re1
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Not in our library10.1017/s1461145710000313

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