Repeated cerebral ischemia induced hippocampal cell death and impairments of spatial cognition in the rat.

We developed a method of causing strong ischemic insult only in vulnerable nerve cells, such as hippocampal cells, without causing hemiplegia or difficulty in moving, by repeating cerebral ischemia for a brief time with a short interval periods. The rats subjected to 10 min of cerebral ischemia exhibited no impairment of spatial cognition at the test trial 7 days after final reperfusion. However, when the 10 min ischemia was repeated twice with a 1 hr interval, the rats exhibited a significant decrease in number of correct choices and increase in number of errors. Three times of repeated cerebral ischemia also induced a significant decrease in the number of correct choices and increase in the number of errors, but there were some rats showing motor difficulty. Cell death was typically observed in the CA1 layer of the hippocampus of rats subjected twice to 10 min of cerebral ischemia. Hippocampal and cortical acetylcholine (ACh) release weas transiently increased during the first and second 10 minutes of ischemia and normalized immediately after recirculation; thereafter, ACh release from these areas gradually decreased and showed a significantly low level at 7 days after recirculation. These results suggest that the repeated cerebral ischemia-induced impairment of spatial memory may be due to the dysfunction of hippocampal and cortical ACh systems and hippocampal cell death. The repeated cerebral ischemia model which produces cell death and ACh dysfunction in the hippocampus is thought to be useful for evaluating new drugs for the treatment of cerebrovascular dementia.