Molecular mechanisms of neuronal death in ischemia

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In order to elucidate the mechanisms of neuronal death in ischemic brain, we investigated the occurrence of DNA fragmentation in gerbil forebrain ischemia, and evaluated the effects of several specific drugs on DNA fragmentation. Forebrain ischemia was produced by transient occlusion of bilateral common carotid arteries for 10 minutes, and DNA fragmentation was confirmed using TUNEL method on cerebral cortex, caudate-putamen, and CA1 region of hippocampus. Administration of Cycloheximide (protein synthesis inhibitor) and aurintricarboxylic acid (endonuclease inhibitor) blocked the occurrence of DNA fragmentation completely in cerebral cortex and partially in caudate-putamen and hippocampus. Similar effects were observed by the administration of GYKI52466 (non-NMDA receptor inhibitor) and leupeptin (calpain inhibitor), but the administration of MK-801 (NMDA receptor inhibitor) showed no blocking effects. 7 nitro-indazole (NOS inhibitor) did show only minor blocking effects and FK 506 showed marked blocking effects.In order to examine the involvement of ICE family, a family of apoptosis-related gene, on ischemic neuronal death, the expression ICE and YAMA gene was measured by northern blotting after rat focal ischemia. The amount of ICE mRNA did not change after ischemia, but Messenger RNA of YAMA was markedly increased 10-20 hours after ischemia.We are now producing the reproduciblc mouse ischemic model to evaluate the involvement of apotosis-related gene on ishemic neuronal death.