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.

Keywords: biological barriers; dysfunction; endothelial; stroke; therapeutic targets; tight junctions; viability.

Figure 1

Schematic illustration summarizing some of the major neurological disorders associated with impairment of the BBB. Note that in some cases, there is a clear, direct causative association where impairment of the BBB is the major prodromal factor for the onset and/or progression of the CNS disorder (e.g., post-ischemic brain injury). In other instances, whether the BBB damage is the causative factor or a derivate effect of the brain disorder further impacting the disease at a later stage is less clear (e.g., Epilepsy).

Figure 2

Schematic illustration of the BBB anatomy. A cross-section of a brain microcapillary segment depicting the innermost luminal compartment composed of a uniform layer of a tightly packed endothelial cell (EC) surrounded by an additional envelope of pericytes (embedded within the basal membrane and astrocytic foot processes which tightly ensheaths the brain microcapillary. The movement of substances across the BBB endothelium is controlled by a multimodal barrier that includes tight junctions (gating barrier to paracellular diffusion of polar molecules); efflux transporters (P-gp, MRPs, BCRP, etc.) with high affinity for lipophilic substances such as cytochrome P450 enzymes, MAO, etc. (metabolic/enzymatic barrier).

Figure 3

Schematic illustration summarizing the effects of brain damage on BBB integrity. The production and activation of MMPs, VEGFs, and ETs are upregulated in various brain cells following brain damage. These factors can then impair the viability and integrity of the BBB by negatively impacting the tight junctions between adjacent endothelial cells.

Figure 4

Structure of blood-brain barrier (BBB) and potential therapeutic targets to restore the BBB viability. Targeting angiogenesis, oxidative stress, cytoskeleton reorganization, and inflammation can effectively protect and potentially restore the viability of the BBB. This includes MMPs and angiogenesis inhibitors (e.g., antibodies targeting VEGF/VEGFR), oxidative stress inhibitors/reducers (such as NOX inhibitors and Nrf2 enhancers) that are promoters of cytoskeleton reorganization (e.g., ROCK inhibitors). Blocking inflammation by targeting immune cells can prevent their recruitment, thus protecting the BBB.