Pre‐ and postconditioning with the mitochondrial ATP‐sensitive potassium (mitoKATP) channel opener BMS‐191095 protects cerebral endothelial cells against oxygen glucose deprivation (OGD)

Abstract

We have shown that the selective mitoKATP channel opener BMS‐191095 protects cultured rat cortical neurons against lethal OGD via acute and delayed preconditioning. We have tested if BMS‐191095 also protects rat brain endothelial cells (RBEC) against lethal OGD, in vitro. Primary RBECs were pretreated with BMS‐191095 (10, 20, 30μM) for 1 day or 1 hour (h) before and 1h immediately after 2h of OGD. OGD reduced viability from 100% to 53±1% but 1 day pretreatment and 1h post‐treatment dose dependently increased viability to 76±2% and 74±1%, respectively (n=16/group; p<0.05). 1h pretreatment was ineffective. Protection could be abolished using the phosphoinositide 3‐kinase (PI3K) inhibitor wortmannin (47±1% and 54±1%; n=16‐16), but not with the selective mitoKATP channel blocker 5‐hydroxydecanoate (66±1% and 71±1%; n=16‐16). Western blot analysis showed a rapid phosphorylation of Akt and ERK 1/2 which peaked at 15 minutes after BMS‐191095 application. Treatment for 24h did not change manganese superoxide dismutase and endothelial nitric oxide synthase levels. In summary, BMS‐191095 prevents OGD‐induced death of RBECs likely by mechanisms involving the PI3K‐Akt and ERK 1/2 pathways.