Study of mechanism of ischemic neuronal death.a molecular biological approach

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We found that there are four types of neuronal death following cerebral ischemia, such as ultra-early-type ischemic neuronal injury in the thalamic reticular nucleus, classical acute ischemic neuronal death due to energy failure, delayd neuronal death which is considered to be related to apoptosis, slowly progressive neuronal death in remote areas from focal cerebral infarction. Mechanisms of teses types of nuronal death after cerebral ischemia were studied as follows.We tried to detect the remote changes using MRI after MCA occlusion in the rat. Then, we found that, in areas remote from a primary ischemic lesion, there are two types of secondary degeneration with MR imaging.Possible induction of mRNAs for proto-oncogene c-myc and s-myc and oncosupressor gene p53, which are known to induce apoptosis, and protooncogene bcl-2, which inhibits apoptosis, was examined following focal ischemia in the rat. The c-myc gene expression was rapidly and markedly induced in a timedependent manner. The results indicate a possibility that high level expression of the c-myc gene may be involved in the ischemic cellular events including apoptosis.It is recently suggested that ceramide, generated by sphingomyelin degradation, plays a role as a second messenger in apoptosis. Level of ceremide, sphingomyelin, cerebroside and gangliosides were determined in rat cerebral cortex during focal ischemia. Ceramide began to increase at 6 hours of ischemia. Aminolinked fatty acids in increased ceramide were composed solely of non-hydroxy fatty acids, and stearic acid was the most prominent. Sphingomyelin, whose aminolinked fatty acids were mostly stearic acid, decreased in a time-dependent manner. The results suggested that ceramide was produced in the cerebral cortex by the breakdown of sphingomyelin during early ischemia.