Protective and regeneratiove responses endogenously induced in the ischemic brain

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Neuronal cells are highly vulnerable against ischemic insult. Because adult neurons are highly differentiated and they can not be divided by themselves, loss of neurons often result in functional deficit in mammalian brains. However, it has recently been shown that neurons and neuronal circuits exhibit protective and regenerative responses in rodent model of experimental ischemia. We previously found ischemic tolerance phenomenon where sublethal ischemic pretreatment enhances resistance in neurons against subsequent ischemic insult. In the present study, we clarified that small ischemic lesion enhanced neuronal resistance against subsequent ischemia for more than 2 weeks while the effect of ischemic pretreatment usually disappears within 2 weeks. We suggested the involvement of reactive astrocytes in extended neuronal protection. Next, we examined the dynamics of neural stem cells after ischemia in the rat hippocampus using four-vessel occlusion model. Proliferating cells were identified in vivo after i. p. administration of bromodeoxyuridine 1 day before sacrifice. After ischemic insult, the stem cells in the subgranular zone of the dentate gyrus in the hippocampus proliferate at 4 days to 14 days after ischemia and differentiate into the neurons 4 weeks later. Understanding of the molecular mechanism underlying these protective and regenerative responses will be important to develop a new strategy for aiming augmentation of resistance against ischemic insult and replacement of injured neurons.