Involvement of MAPK cascades in ischemic tolerance in neurons

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Molecular mechanisms of ischemic neuronal death and ischemic tolerance in brain remain to be elucidated. We studied in this project how mitogen-activated protein kinases (MAPKs) cascades would be involved in cerebral ischemia using immunoblotting and immunohistochemistry in rodent models. In gerbil hippocampus, ERK, JNK and p38 were strongly activated (that is, phosphorylated) with specific temporal and spatial patterns after transient forebrain ischemia, and a specific inhibitor for p38 attenuated ischemic neuronal death in CA1 of the hippocampus. MAPK cascades were also activated in rat striatum after mitochondrial impairment by 3-nitropropionic acid and in mouse hippocampus after transient forebrain ischemia. Mild ischemia, which induced ischemic tolerance in gerbil hippocampus, also activated MAPK cascades and an inhibitor of p38 reduced ischemic tolerance. These data suggested that p38 might play a significant role in neuronal death and survival after cerebral ischemia and that control of MAPK cascades would modify clinical outocomes of stroke patients.