We have previously demonstrated that KR-33028, a novel inhibitor of Na+/H+ exchanger-1 (NHE-1), exerts neuroprotective effects during cerebral ischemia. In the present study, we investigated whether KR-33028 elicits cerebrovascular protective effects against ischemia-induced blood-brain barrier (BBB) dysfunction in vivo and in vitro.
Effects of KR-33028 on ischemia/hypoxia-induced BBB dysfunction in vivo were evaluated by examining brain water content, Evans blue extravasation and tight junction(TJ) alteration in a rat cerebral ischemia model. In vitro effects of KR-33028 on ischemia/hypoxia-induced BBB dysfunction were investigated by determining permeability of Evans blue-albumin or [14C] sucrose, TJ alteration in brain microvascular endothelial cells (bEnd.3 cells). In addition, the intracellular Ca2+ level were measured using an imaging technique.
KR-33028 inhibited the activation of NHE-1 induced by intracellular acidosis in bEnd.3 cells. KR-33028 ameliorated brain edema in rat brain ischemia model. KR-33028 also ameliorated BBB hyperpermeability and disruption of occludin and ZO-1 induced by ischemia/hypoxia in vivo and in vitro. Furthermore, KR-33028 prevented hypoxia-induced subcellular redistributions of occludin and ZO-1 in vitro. Hypoxia-induced increases in intracellular Ca2+ levels in vitro were reduced by KR-33028.
These findings suggest that KR-33028 ameliorates BBB hyperpermeability and TJs alteration during ischemia/hypoxia, and that KR-33028 has a therapeutic potential to prevent BBB dysfunction after brain ischemia.
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