Critical role of actin in modulating BBB permeability

A major obstacle in the treatment of degenerative manifestations and debilitating diseases in the central nervous system (CNS) lies in the impediment of drug delivery into these tissues. The impediment is due to a membrane barrier referred to as the blood–brain barrier (BBB). It is known that the BBB is a unique membranous structure in brain capillaries that tightly segregates the brain from systemic blood circulation. It is imperative to have a thorough understanding of the molecular components and their integrated function of this barrier to develop effective therapeutics for CNS disorders and diseases. Although there are other cell and biochemical properties that underlie this barrier function, it is well established that the barrier is mainly made up of the physical elements of tight junction (TJ) complex. The major constituents of TJ, such as occludin, claudins, zonula occludens (ZOs) and junctional adhesion molecule (JAM) have been subjects of intensive studies and reviews. However, after examining currently proposed models, we have come to believe that a cytoskeletal component-actin may play a critical role in interacting TJ molecular constituents and modulating functional TJ complex. In this review, we will discuss the correlation of temporal and spatial distribution and remodeling of actin filaments with altering integrity of TJ complexes in various systems and present a hypothesis to depict its potential role in modulating BBB permeability.