Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview

Abstract

The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity is vital to maintain the homeostasis of the brain microenvironment by controlling the passage of substances and regulating the trafficking of immune cells between the blood and the brain. The BBB is primarily composed of highly specialized microvascular endothelial cells. These cells’ special features and physiological properties are acquired and maintained through the concerted effort of hemodynamic and cellular cues from the surrounding environment. This complex multicellular system, comprising endothelial cells, astrocytes, pericytes, and neurons, is known as the neurovascular unit (NVU). The BBB strictly controls the transport of nutrients and metabolites into brain parenchyma through a tightly regulated transport system while limiting the access of potentially harmful substances via efflux transcytosis and metabolic mechanisms. Not surprisingly, a disruption of the BBB has been associated with the onset and/or progression of major neurological disorders. Although the association between disease and BBB disruption is clear, its nature is not always evident, specifically with regard to whether an impaired BBB function results from the pathological condition or whether the BBB damage is the primary pathogenic factor prodromal to the onset of the disease. In either case, repairing the barrier could be a viable option for treating and/or reducing the effects of CNS disorders. In this review, we describe the fundamental structure and function of the BBB in both healthy and altered/diseased conditions. Additionally, we provide an overview of the potential therapeutic targets that could be leveraged to restore the integrity of the BBB concomitant to the treatment of these brain disorders.

Glyoxal Fixation Is Optimal for Immunostaining of Brain Vessels, Pericytes and Blood-Brain Barrier Proteins

“…The barrier properties of these brain endothelial cells notably depend on tight junctions (TJ) between adjacent cells: TJs are dynamic structures consisting of several transmembranes and membrane-associated cytoplasmic proteins [ 40 ]. Moreover, several studies have reported leaky BBB is associated with the loss of integrity in TJs [ 41 ]. Our analysis suggests that the immunostainings performed after glyoxal fixation can more readily allow the identification of TJ proteins ( Figure 3 ).…”

Glutamate Efflux across the Blood–Brain Barrier: New Perspectives on the Relationship between Depression and the Glutamatergic System

“…Although the exact mechanisms of BBB permeability have not yet been clearly elucidated, BBB dysregulation has negative effects on a number of conditions, including stroke, TBI, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and schizophrenia [ 73 , 74 ], known to be a major contributor to the pathology of CNS disorders [ 75 ]. Specifically, glutamate excitotoxicity, in which cell death occurs as a result of excessive glutamate release from neurons and glial cells, contributes to the influx of glutamate in the BBB.…”

“…Other neurological conditions that are caused or exacerbated by BBB disruption and glutamate excitotoxicity and have an association with depression include Parkinson’s disease [ 84 ], Huntington’s disease [ 85 ], amyotrophic lateral sclerosis [ 86 , 87 ], multiple sclerosis [ 75 , 88 ], Alzheimer’s disease [ 89 , 90 , 91 , 92 ], epilepsy [ 93 , 94 , 95 ], aging [ 77 ] and schizophrenia [ 96 , 97 ]. There are likely interpolations to be made to similar conditions for which the association between BBB or depression lacks conclusive data [ 75 ], such as in hepatic encephalopathy [ 98 ] and brain tumors [ 99 ]. The idea of glutamatergic involvement in depression present during these conditions requires additional research.…”

Blood-Brain Barrier Alterations and Edema Formation in Different Brain Mass Lesions

“…Reactive astrocytes and inflammatory cells are responsible for the production of VEGF, which affects BBB integrity in brain tissue surrounding the abscess (Vaquero et al, 2001). Upregulation of VEGF in reactive astrocytes leads to downregulation of claudin-5 and occludin, resulting in BBB disruption and the development of brain edema (Archie et al, 2021).…”