Neuroprotection against Cerebral Ischemic Damage : A role for caspase

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The purpose of this study was to clarify the molecular mechanisms of cerebral ischemia-induced neuronal death, and to develop the strategy for neuroprotection from cerebral ischemia. Special attention was focused on apoptosis induced by caspase activation and inflammatory response. The findings obtained in this study using rat models of cerebral ischemia were as follows. (1) Postischemic expressions of caspase 3, caspase 8, Fas ligand, and TNFα were examined. Caspase 3 was upregulated in neurons in penumbra, but otherwise we have not obtained constant results. We are conducting further experiments. (2) An immunophilin FK506 binding protein-12 (FKBP12), which also modulates intracellular calcium channel receptors, was localized predominantly in neurons, and decreased rapidly after cerebral ischemia, but was upregulated in surviving neurons in the penumbra and inflammatory cells invading the area of infarction. (3) Microglial response factor-1 (MRF-1) is a newly isolated gene upregulated in response to microglial activation. MRF-1 was upregulated following cerebral ischemia and was present in all the cell types of phagocyte/macrophage lineage (microglia, monocytes/macrophages, and perivascular cells). (4) A cytokine macrophage migration inhibitory factor (MIF), which was present in normal neurons and astrocytes, decreased rapidly after cerebral ischemia, but was upregulated in surviving neurons in the penumbra and inflammatory cells invading the area of imfarction. (5) Proliferating cell nuclear antigen (PCNA) was not present in normal brains and was detected in a number of activated microglia and invading macrophages, and in a small number of reactive astrocytes.