Blood-Brain Barrier Integrity and Glial Support: Mechanisms that can be Targeted for Novel Therapeutic Approaches in Stroke

Abstract

The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. Additionally, the BBB is the most significant obstacle to effective CNS drug delivery. It possesses specific charcteristics (i.e., tight junction protein complexes, influx and efflux transporters) that control permeation of circulating solutes including therapeutic agents. In order to form this “barrier,” brain microvascular endothelial cells require support of adjacent astrocytes and microglia. This intricate relationship also occurs between endothelial cells and other cell types and structures of the CNS (i.e., pericytes, neurons, extracellular matrix), which implies existence of a “neurovascular unit.” Ischemic stroke can disrupt the neurovascular unit at both the structural and functional level, which leads to an increase in leak across the BBB. Recent studies have identified several pathophysiological mechanisms (i.e., oxidative stress, activation of cytokine-mediated intracellular signaling systems) that mediate changes in the neurovascular unit during ischemic stroke. This review summarizes current knowledge in this area and emphasizes pathways (i.e., oxidative stress, cytokine-mediated intracellular signaling, glial-expressed receptors/targets) that can be manipulated pharmacologically for i) preservation of BBB and glial integrity during ischemic stroke and ii) control of drug permeation and/or transport across the BBB in an effort to identify novel targets for optimization of CNS delivery of therapeutics in the setting of ischemic stroke.

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

“…Our investigation revealed that bystander microglia exposed to overlays from infected astrocytes produce significantly more IL-1α, IL-1β, IL-6, and IL-8 as compared to the directly infected cells. These pro-inflammatory cytokines are strongly linked with BBB damage, which indicates that BBB permeability may be the result of bystander cell inflammation rather than direct infected cells [47–49]. This cytokine induction recapitulates in our primary cell model and occurs as early as 1 hour post infection, which underscores the need for an effective therapeutic that can mitigate this massive pro-inflammatory cytokine response.…”

Age-associated physiological and pathological changes at the blood–brain barrier: A review

“…Additionally, matrix proteins have been shown to influence the expression of TJ proteins, such as occludin, suggesting that the extracellular matrix plays a role in maintaining TJ protein integrity. 15,26,30 Astrocytes Astrocytes are the most abundant cell type in the brain and display a fibroblast-like morphology within grey matter 15,31 ; however, this morphology can be influenced by their CNS location and associations with other cell types that are in close proximity. 32 Astrocyte end-feet cover over 99% of cerebral capillaries, 33 leading to critical cell-cell interactions that directly modulate and regulate BBB characteristics.…”

Gyógyszertranszporterek szerepe a központi idegrendszerben

“…A központi idegrendszerben legfontosabb szerepet ját-szó P-gp transzporter szerepét Murozono és mtsai mdr1 knockout egereken tanulmányozták. Kísérleteik alapján az mdr1 génnel nem rendelkező állatokon sokkal kisebb volt az infarktus térfogata középagyi artéria okklúzióját követően [47,48], mint a vad típusú egereken. Farmakológiai megközelítésben pedig a P-gp inhibitor cyclosporin A alkalmazása drámaian csökkentette az infarktus nagyságát stroke-os állatokon [49].…”