TI - The Akt signaling pathway contributes to postconditioning's protection against stroke ; the protection is associated with the MAPK and PKC pathways . AB - We previously reported that ischemic postconditioning with a series of mechanical interruptions of reperfusion reduced infarct volume 2 days after focal ischemia in rats . Here , we extend this data by examining long-term protection and exploring underlying mechanisms involving the Akt , mitogen-activated protein kinase ( MAPK ) and protein kinase C ( PKC ) signaling pathways . Post-conditioning reduced infarct and improved behavioral function assessed 30 days after stroke . Additionally , postconditioning increased levels of phosphorylated Akt (Ser473) as measured by western blot and Akt activity as measured by an in vitro kinase assay . Inhibiting Akt activity by a phosphoinositide 3-kinase inhibitor , LY294002 , enlarged infarct in postconditioned rats . Postconditioning did not affect protein levels of phosphorylated-phosphatase and tensin homologue deleted on chromosome 10 or -phosphoinositide -dependent protein kinase-1 ( molecules upstream of Akt ) but did inhibit an increase in phosphorylated-glycogen synthase kinase 3beta , an Akt effector . In addition , postconditioning blocked beta-catenin phosphorylation subsequent to glycogen synthase kinase , but had no effect on total or non-phosphorylated active beta-catenin protein levels . Furthermore , postconditioning inhibited increases in the amount of phosphorylated-c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in the MAPK pathway . Finally , postconditioning blocked death-promoting deltaPKC cleavage and attenuated reduction in phosphorylation of survival-promoting epsilonPKC . In conclusion , our data suggest that postconditioning provides long-term protection against stroke in rats . Additionally , we found that Akt activity contributes to postconditioning's protection ; furthermore , increases in epsilonPKC activity , a survival-promoting pathway , and reductions in MAPK and deltaPKC activity ; two putative death-promoting pathways correlate with postconditioning's protection .