Elsevier

Neurobiology of Disease

Volume 32, Issue 2, November 2008, Pages 200-219
Neurobiology of Disease

Review
Blood-brain barrier tight junction permeability and ischemic stroke

https://doi.org/10.1016/j.nbd.2008.08.005Get rights and content

Abstract

The blood-brain barrier (BBB) is formed by the endothelial cells of cerebral microvessels, providing a dynamic interface between the peripheral circulation and the central nervous system. The tight junctions (TJs) between the endothelial cells serve to restrict blood-borne substances from entering the brain. Under ischemic stroke conditions decreased BBB TJ integrity results in increased paracellular permeability, directly contributing to cerebral vasogenic edema, hemorrhagic transformation, and increased mortality. This loss of TJ integrity occurs in a phasic manner, which is contingent on several interdependent mechanisms (ionic dysregulation, inflammation, oxidative and nitrosative stress, enzymatic activity, and angiogenesis). Understanding the inter-relation of these mechanisms is critical for the development of new therapies. This review focuses on those aspects of ischemic stroke impacting BBB TJ integrity and the principle regulatory pathways, respective to the phases of paracellular permeability.

Introduction

The blood-brain barrier (BBB) is a diffusion barrier, consisting of an interdependent network of cells designed to segregate the central nervous system (CNS) from the systemic circulation. One of the primary responsibilities of the BBB is the strict regulation of paracellular permeability. In this regard, the endothelial tight junctions (TJs) of the capillary are the primary mediators, limiting paracellular movement of solutes, ions, and water. These TJs are regulated via highly specialized proteins, which can be modulated by numerous intracellular and extracellular signaling pathways. Although the physiological properties of the TJs have been intensely investigated over the past few decades, less is known concerning their regulation under pathological conditions.

During ischemic stroke and subsequent reperfusion, the TJs of the BBB are disrupted, resulting in the increase of vascular derived substances into the brain. However, such disruption is not a singular event. TJ permeability occurs in phases, and although these phases are interdependent they are mediated through different mechanisms. As such, through delineation of these processes we will not only gain a greater understanding of TJ alteration and regulation, but also gain valuable insight with regard to therapeutic applications.

This review focuses on the emerging concepts surrounding BBB TJs with regard to ischemic stroke. It will begin with addressing the functional anatomy of the BBB, followed by clarification of the endothelial TJs and associated regulatory proteins. It will then focus on the ischemia and reperfusion (I/R) dependent phases of BBB paracellular permeability. Next it will highlight the molecular pathways and principle mediators involved in BBB TJ changes, correlated to the time-course of I/R events. Lastly, it will address the clinical and drug development implications.

Section snippets

Functional anatomy

The BBB has long been described as the gate-keeper of the CNS, maintaining the fragile homeostasis of the brain. The unique functionality and morphology of the BBB is attributed to multiple factors. In addition to endothelial cells, the BBB is composed of pericytes, astrocytes, neurons, and extracellular-matrix (ECM), which have been collectively redefined as the neurovascular-unit (NVU) (Fig. 1A). The individual components of the NVU work in concert to regulate microvascular permeability, ion

Tight junctions

Much of what is currently understood regarding endothelial TJs has been derived from epithelial cell examinations, owing to the significant degree of structural and functional similarities. Nevertheless, BBB endothelial TJs hold many unique attributes, which may be more appropriately correlated with the endothelium of other systems when evaluating dynamic regulation and paracellular permeability. Thus, it should be understood that much of the current theory regarding BBB TJ regulation is based

Ischemic stroke impact on BBB permeability and tight junction regulation

Stroke ultimately involves the destruction and/or dysfunction of brain cells, leading to clinically definable neurological deficits. Ischemic stroke consists of two distinctive periods of pathological impact, ischemia and reperfusion. Both ischemia and reperfusion can be further delineated into a series of interdependent biochemical and cellular events that evolve over minutes to days. With this understanding, BBB TJ alterations can be divided into time-dependent phases, based on states of

Clinical and drug development implications

As addressed, the I/R induced phases of TJ permeability are the result of multiple interdependent events. Appropriately matching the mechanisms of action with the time-frame of events can allow for more effective hospital treatment and drug development. In this regard, it is necessary to be more critical in our approach to ischemic stroke modeling, especially within the context of drug evaluations. For example, assessment of BBB paracellular permeability as a primary measure of drug efficacy

Conclusions

It has become apparent that the processes governing BBB TJ permeability during ischemic stroke are extremely complex. Yet, through delineation of the phases of permeability, we are better able to clarify the molecular mechanisms of TJ regulation. As these phases have many unique characteristics, they provide the opportunity to more accurately tailor time-dependent therapeutics. Furthermore, there are strong implications for BBB TJ proteins acting as primary mediators of angiogenesis and

Acknowledgment

This work was supported by SIUE-FUR Grant # 729089.

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