Unlike astrocytes, they only partially cover the microvessel, but their processes can span several endothelial cells. Pericytes are embedded in the basement membrane in the abluminal surface of brain microvessels. Although astrocytes are important for the development and maintenance of the BBB, recent evidence suggests that it is pericytes that are critical for the formation and induction of the BBB and are implicated in contributing to the progression of CNS disease. These in vitro studies have provided a great deal of information to support the role of astrocytes in up-regulating many BBB features, including low paracellular permeability and up-regulation of tight junctions, transporters and enzymes. Most in vitro BBB models use astrocytes in co-culture to take advantage of the astrocyte-secreted factors to increase the tightness/TEER of brain endothelial cells. This close proximity and the ability of astrocytes to secrete soluble factors allow them to induce BBB phenotype in brain endothelial cells. Brain capillaries are surrounded by perivascular endfeet of astrocytes and therefore astrocytes occupy a strategic position between brain capillaries and neurons. However, the critical importance of astrocytes in the induction and maintenance of BBB structure and function has long been established (reviewed in ). In addition, brain endothelial cells lack fenestrations, have very few pinocytotic vesicles, and reduced expression of adhesion molecules, which limit immune cell infiltration (for a comprehensive review on the BBB see ). The presence of complex intercellular tight junctions results in high transendothelial electrical resistance (TEER) in brain microvessels, compared with peripheral microvessels. Tight junctions also act as a ‘fence’ to segregate these transporters to the apical and basal domains, so that the endothelium can act as a polarised barrier to prevent free movement of the transporters. An array of specific transporters, receptors and enzymes controls the molecular traffic via the transcellular route and permit the passage of nutrients and removal of waste products across the BBB. These highly specialised endothelial cells have intercellular tight junctions such as claudins, occludin, zonula occludens, and junctional adhesion molecules that control the movement of molecules through the paracellular pathway (‘gate function’) by showing size and charge selectivity. The blood–brain barrier (BBB) formed by brain capillary endothelial cells is the dynamic physiological structure that protects the brain to maintain normal neuronal function. Therefore, innovative strategies to carry therapeutics across the BBB and novel models to screen drugs, and to study the complex, overlapping mechanisms of BBB disruption are urgently needed. The BBB's crucial role in protecting the brain is also the bottleneck in central nervous system drug development. This review evaluates and summarises some of the latest research on the role of the BBB during neurological disease and infection with a focus on the effects of inflammation and flow disturbances on the BBB. It is worth noting that timing and extent of BBB disruption play an important role in the process of any repair of brain damage and treatment strategies. While a transient or minor disruption to the barrier function could be tolerated, chronic or a total breach of the barrier can result in irreversible brain damage. In particular, in ischaemic stroke, both inflammation and flow disturbances contribute to BBB disruption, leading to devastating consequences. Among other mechanisms, inflammation and/or flow disturbances are major causes of BBB dysfunction in neurological infections and diseases. BBB dysfunction is implicated in many neurological diseases such as stroke, Alzheimer's disease, multiple sclerosis, and brain infections. Dysfunction of this highly complex and regulated structure can be life threatening. The BBB plays an extremely important role in supporting normal neuronal function by maintaining the homeostasis of the brain microenvironment and restricting pathogen and toxin entry to the brain. A healthy brain is protected by the blood–brain barrier (BBB), which is formed by the endothelial cells that line brain capillaries.
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