Abstract
The members of the mitogen-activated protein kinase (MAPK) which are characterized as prolinedirected serine-threonine-protein kinases have crucial roles in transducing stress-related signals in eukaryotic cells and regulate cell death and survival. Recent studies have demonstrated that the members of the MAPK family, in particular p38 are activated following ischemia/reperfusion and suggest that this kinase signaling pathway may be important and responsible for tissue injury after ischemia/reperfusion. We investigated the activation of p38 in various brain ischemic models to clarify the roles of this stress kinase during brain ischemia.
To clarify the role of p38 in ischemic tolerance, a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia, we used a gerbil model of 2-minute ischemia folio wed by 5-minute ischemia. After the 2-minute global ischemia, active p38 immunoreactivity was enhanced at 6 hours of reperfusion and continuously demonstrated 72 hours after ischemia in CA1 neurons. Pretreatment with SB203580, an inhibitor of active p38, reduced the ischemic tolerance effect in a dosedependent manner. Immunoblot analysis indicated that the phosphorylation pattern of p38 kinase in the hippocampus induced by lethal ischemia was altered by preceding sublethal ischemia (preconditioning). These findings indicate that p38 pathway may play important roles in neuronal death and survival during brain ischemia. Components of the p38 pathway are important target molecules for clarifying the mechanism of ischemic brain injury.
