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

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.

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…In addition, inflammatory cytokines can increase extracellular glutamate by decreasing excitatory amino-acid transporters, which are responsible for glutamate reuptake, and increasing glutamate release from astrocytes and activated microglia (Dantzer and Walker, 2014;Takaki et al, 2012;Tilleux and Hermans, 2007). This inflammationmediated increase in glutamate release and NMDA activation can lead to excitotoxicity in the brain (Guillemin, 2012;Guillemin et al, 2003), further increasing oxidative stress and potentially contributing to the effects on BH4 and DA synthesis (Felger and Miller, 2012;Najjar et al, 2013), as described above (Figure 2). In addition, increased xanthurenic acid, a metabolite of the kynurenine pathway upstream of QUIN, has been shown to directly attenuate BH4 biosynthesis by inhibition of sepiapterin reductase (Haruki et al, 2016).…”

Blood cells and endothelial barrier function

“…Consequently, BBB disruption in the brain can be associated with more profound local and systemic detrimental effects than observed in other tissues following endothelial barrier failure. The fact that Major depressive disorder 162 1 Chronic obstructive pulmonary disease (COPD).…”

Activation of p38-mitogen-activated protein kinase contributes to ischemia reperfusion in rat brain

“…The BBB secures the brain's immune-privileged status by restricting the entry of peripheral inflammatory mediators such as cytokines and antibodies. The BBB is composed of specialized endothelial cells of the cerebral microvasculature, surrounding pericytes, astrocytic endfeet, perivascular macrophages, microglia, the basement membrane, and cell-cell junctions (Keller, 2013;Najjar et al, 2013;Hsu and Kanoski, 2014;Williams et al, 2014). As mentioned above, inflammation-mediated damage leads to BBB hyperpermeability, and S100 calcium-binding protein A4 (S100A4) may play a role in the induction of BBB disruption caused by the inflammation associated with rheumatoid arthritis.…”