Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke
- PMID: 22574987
- PMCID: PMC3918413
- DOI: 10.2174/138161212802002625
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 brain 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. Targeting these pathways present a novel opportunity for optimization of CNS delivery of therapeutics in the setting of ischemic stroke.
Conflict of interest statement
Part of the information that appears in this article has been adapted from Ronaldson & Davis.
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References
-
- Hartz AM, Bauer B. Regulation of ABC transporters at the blood-brain barrier: new targets for CNS therapy. Mol Interv. 2010;10(5):293–304. - PubMed
-
- Witt KA, Mark KS, Hom S, Davis TP. Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol. 2003;285(6):H2820–H2831. - PubMed
-
- Brown RC, Mark KS, Egleton RD, Davis TP. Protection against hypoxia-induced blood-brain barrier disruption: changes in intracellular calcium. Am J Physiol Cell Physiol. 2004;286(5):C1045–C1052. - PubMed
-
- Mark KS, Burroughs AR, Brown RC, Huber JD, Davis TP. Nitric oxide mediates hypoxia-induced changes in paracellular permeability of cerebral microvasculature. Am J Physiol Heart Circ Physiol. 2004;286(1):H174–H180. - PubMed
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