Elsevier

Progress in Neurobiology

Volume 68, Issue 5, December 2002, Pages 311-323
Progress in Neurobiology

Junctional complexes of the blood–brain barrier: permeability changes in neuroinflammation

https://doi.org/10.1016/S0301-0082(02)00128-4Get rights and content

Abstract

A wide range of central nervous system (CNS) disorders include neuroinflammatory events that perturb blood–brain barrier (BBB) integrity. Mechanisms by which the BBB responds to physiological and pathological stimuli involve signaling systems in the tight and adherens junctions of the cerebral endothelium. In this review, we examine the molecular composition and regulatory mediators that control BBB permeability and assess how these mediators may be dysregulated in stroke, multiple sclerosis, brain tumors, and meningioencephalitis. An understanding of these molecular substrates in BBB regulation may lead to new approaches for enhancing CNS drug delivery and ameliorating brain edema after injury and inflammation.

Introduction

The blood–brain barrier (BBB) is a complex cellular system comprising cerebral endothelial cells resting on the basal lamina. The endothelial cells of the cerebral capillaries and post-capillary venules form the basis of the BBB, the main function of which is to regulate the entry of blood-borne molecules into the brain and to preserve ionic homeostasis within the brain microenvironment. Passage of molecules across the endothelial cells of the BBB can occur through the cells (the transcellular path) or between adjacent cells (the paracellular pathway). The transcellular path can involve various mechanisms including passive diffusion of lipophilic compounds, receptor-mediated shuttling and trancytosis. The paracellular passage, however, is not assisted by such mechanisms; instead the ions and solutes diffuse between adjacent cells down their concentration gradient. This paracellular space is almost completely obstructed by tight junctions, which are cell–cell junctional complexes in the apical region of cell membranes. Since the junctional complex controls passage through the paracellular space, it represents a central functional component of BBB regulation. This review will focus on the molecular structure and location of the junctional complexes, how they are regulated to induce changes in permeability and the mechanisms involved in neuroinflammatory conditions that lead to increases in BBB permeability.

Understanding the molecular composition and regulation of the BBB is important for at least two reasons: (1) as a basis for designing new methods to penetrate the BBB, in order to deliver therapeutics directly into target tissue in brain and (2) to develop means of closing the BBB in conditions such as stroke, multiple sclerosis, and brain tumors. Currently, there are no treatments to correct these permeability changes that can lead to cerebral edema and the associated increase in intracranial pressure, which can lead to death. With the recent progress made in defining the mechanisms involved, as described in this review, possible therapeutic targets can be identified.

Section snippets

Blood–brain barrier

Maintenance of the fragile extracellular microenvironment in the neuronal parenchyma is essential for normal brain function. The BBB is the structure responsible for this protection against noxious chemicals, variation in blood composition and breakdown of the concentration gradient. In higher vertebrates, the BBB is made up of brain microvessel endothelial cells, which are estimated to form an area of 20 m2 for the average 1300 g human brain. BBB endothelial cells are distinct from peripheral

Location

Tight and adherens junctions together form the junction complex between adjacent endothelial cells (summarized in Fig. 1). A characteristic feature of endothelial tight junctions in the brain is their intercalation with components of adherens junctions along the entire length of the junctional area (Schulze and Firth, 1993).

Tight junctions

Tight junctions are located in the most apical section of the plasma membrane of adjacent cells. By forming a seal to prevent solutes from paracellular diffusion, tight

BBB dysregulation in neuroinflammation

Under basal physiological conditions the brain microvessel endothelium acts as a barrier to the immune system limiting the entry of monocytes, lymphocytes and other leukocytes. Nevertheless, in pathological situations such as stroke or multiple sclerosis, a disruption in BBB integrity occurs, associated with the transmigration of numerous activated neutrophils, lymphocytes or monocytes (Perry et al., 1997).

Cramer et al. (1992) reported that neutrophils can transmigrate without affecting

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has been implicated in endothelial cell proliferation, permeability and angiogenesis (Dvorak et al., 1995, Senger et al., 1996). VEGF is a homodimeric 45-kDa glycoprotein that is secreted by a variety of cells. It stimulates endothelial growth and permeability increases by interacting with two plasma membrane receptors on vascular endothelial cells. The two receptors, fms-like tyrosine kinase (FLT-1) and the

Modifying the BBB

In contrast to the disruptive effects of BBB leakage after brain injury and neuroinflammation, the inverse problem also exists, i.e. how to penetrate the BBB for delivering therapeutic compounds. The fundamental barrier is manifested by the tight junctions between cerebral endothelium and the paucity of transcellular transport. Drug delivery through the BBB is a rapidly moving field and a complete review is beyond the scope of the present article; the reader is referred to more detailed reviews

Conclusions

Recent studies, described in this review, demonstrate the complex and dynamic nature of the junctional complexes of the BBB. Local chemical signals trigger intricate signaling mechanisms, lead to cytoskeletal reorganization in the junctional complexes of the BBB, and ultimately modulate paracellular permeability. By these means, the BBB can partially protect the brain’s fragile extracellular microenvironment that is essential for normal brain function. In pathological conditions, BBB

Acknowledgements

Supported in part by the following grants from NIH, R01-NS37074, R01-NS38731, R01-NS40529, and P50-NS10828.

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