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

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Journal of Neuroinflammation

, 10:906

First Online: 01 December 2013Received: 15 August 2013Accepted: 15 November 2013


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.

KeywordsMajor depressive disorder Blood-brain barrier Neurovascular unit Neuroinflammation Oxidative stress Nitric oxide synthase eNOS uncoupling Peroxynitrite AbbreviationsAQP4Aquaporin 4



CBFCerebral blood flow

COX2Cyclooxygenase 2

CRHCorticotropin-releasing hormone

CSFCerebrospinal fluid

CTComputed tomography


eNOSEndothelial nitric oxide synthase

EAATExcitatory amino acid transporter

FcImmunoglobulin constant region

H2O2Hydrogen peroxide

HO-Hydroxyl radical

ICAM-1Intercellular adhesion molecule 1


iNOSInducible nitric oxide synthase

MAPMicroglial activation and proliferation

MDDMajor depressive disorder

MRIMagnetic resonance imaging

mGluRMetabotropic glutamate receptor

MMPsMatrix metalloproteinases

NADPHNicotinamide adenosine dinucleotide phosphate

Na+-K+ ATPaseSodium-potassium adenosine triphosphates

NFκBNuclear factor κB

NMDARN-methyl-D-aspartate receptor

NONitric oxide



PETPositron emission tomography

PLA2Phospholipase A2

RNSReactive nitrogen species

ROSReactive oxygen species

RURRelative uptake ratio

SOD-1Superoxide dismutase 1

SPECTSingle photon emission computed tomography

SSRISelective serotonin reuptake inhibitor

ThT helper

TNFαTumor necrosis factor α

TRegCD4CD25FOXP3 T regulatory

VCAM-1Vascular cell adhesion molecule 1.

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Autor: Souhel Najjar - Daniel M Pearlman - Orrin Devinsky - Amanda Najjar - David Zagzag


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