Basic research for cerebral ischemia therapy based on ischemic tolerance

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It has been reported that prior sublethal ischemia in brain tissue induces the phenomenon of ischemic tolerance to subsequent lethal ischemic stress in the hippocampal CA1 region. We recently reported the activation of MAPK cascades after the administration of 3-NP, which is a mitochondrial succinate dehydrogenase inhibitor, at a dose that induced ischemic tolerance in the gerbil hippocampus, but it remains to be shown whether or not the activations of MAPK cascades may affect the ischemic tolerance phenomenon induced by sublethal ischemia. In previous studies, we obtained evidence suggesting that p38 was activated in the gerbil hippocampus after 5-minute transient forebrain ischemia in vivo and that the inhibition of the activity of p38 protected against delayed neuronal death in CA1 pyramidal cells. We investigated the activation of p38 mitogen-activated protein kinase in the gerbil hippocampus by Western blotting and immunohistochemistry to clarify the role of p38 kinase in ischemic tolerance. Immunoblot analysis indicated the activation of p38 in the hippocampus after 2 minutes of global sublethal ischemia. After this 2-minute global ischemia, immunoreactivity indicating active p38 was enhanced at 6 hours of reperfusion and continuously demonstrated 72 hours after ischemia in CA1 and CA3 neurons. Pretreatment with SB203580, an inhibitor of active p38, 30 minutes before the 2-minute ischemia reduced the ischemic tolerance effect in a dose-dependent manner. Genetic disruption of STAT1, a targeted molecule of p38, reduced ischemic damage in a mice ischemic model. These findings suggest that p38 may contribute to both ischemic damage and tolerance in CA1 neurons of the hippocampus and that components of the p38 cascade can be target molecules to modify neuronal survival after ischemia.