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.
Highlights
Major depressive disorder (MDD) is the second leading global cause of years lived with disability [1], with about one-third of patients with MDD failing two or more conventional antidepressant drug trials within the first year of treatment [2,3]
We review emerging clinical and experimental evidence implicating oxidative stress, endothelial nitric oxide synthase (eNOS) uncoupling, and reduced endothelial nitric oxide (NO) levels in the pathophysiology of peripheral vascular endothelial dysfunction associated with MDD
The authors attributed BH4 augmenting the antidepressant effects of Selective serotonin reuptake inhibitor (SSRI) to direct activation of the rate-limiting enzymes of monoamine synthesis, we suggest that these effects may be related to the ability of BH4 to reverse eNOS uncoupling
Summary
Major depressive disorder (MDD) is the second leading global cause of years lived with disability [1], with about one-third of patients with MDD failing two or more conventional antidepressant drug trials within the first year of treatment [2,3]. In neurological disorders associated with neurovascular dysfunction, oxidative stress can increase BBB permeability through several mechanisms (Table 1), which include: (a) activation of metalloproteinase (MMP)-2/9 directly or indirectly through proinflammatory cytokines [39]; (b) downregulation of endothelial expression of E-cadherin [38]; (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 [38,41,103,104]; (d) alteration of endothelial cytoskeletal structure; (e) induction of endothelial NMDAR subunit expression such as NMDA receptor subunit 1 (NR1) subunit, leading endothelial excitotoxicity [40]; and (f) impairment of vascular endothelial mitochondrial oxidative metabolism [11,123] The relevance of these mechanisms to the neurobiology of MDD, remains unclear (Table 1 and Figure 2). Powered randomized controlled trials investigating the effects of anti-inflammatory agents and antioxidants in MDD [4,90] should assess their effects on cerebral microvascular endothelial functions (for example, by utilizing techniques that measure peripheral vascular dilatory response [182] and cerebral perfusion [90]), as well as the relationship between the extent of endothelial dysfunction and the severity of depressive symptoms
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