Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a re
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JOURNAL OF NEUROINFLAMMATION
REVIEW
Open Access
Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence Souhel Najjar1,2*, Daniel M Pearlman1,3, Orrin Devinsky2, Amanda Najjar4 and David Zagzag4,5
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. Keywords: Major depressive disorder, Blood-brain barrier, Neurovascular unit, Neuroinflammation, Oxidative stress, Nitric oxide synthase, eNOS uncoupling, Peroxynitrite
Background 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]. Current evidence suggests that the pathophysiology of MDD is multifactorial, involving heterogeneous and inter-related mechanisms that affect * Correspondence: [email protected] 1 Department of Neurology, Neuroinflammation Research Group, Epilepsy Center Division, NYU School of Medicine, New York, NY 10016, USA 2 Department of Neurology, NYU Comprehensive Epilepsy Center, NYU School of Medicine, New York, NY 10016, USA Full list of author information is available at the end of the article
genetic, neurotransmitter, immune, oxidative, and inflammatory systems [4]. Supporting this interpretation, whereas biomarke
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