INDUCTION OF C-FOS AND C-JUN GENE-PRODUCTS AND HEAT-SHOCK PROTEIN AFTER BRIEF AND PROLONGED CEREBRAL-ISCHEMIA IN GERBILS

Background and Purpose Proto-oncogene activation and induction of heat shock protein (HSP) occur in response to various stimuli to brain, bu t the role in neuronal survival after cerebral ischemia remains uncert ain. We compared the extent of insults and induction of c-fos and c-ju n gene products (c-FOS and c-JUN) as well as HSP in ischemic and posti schemic gerbil brains immunohistochemically. Methods Common carotid ar teries of Mongolian gerbils were occluded for 5 or 15 minutes and reci rculated for 0 minutes to 7 days. Antibodies for c-FOS, c-JUN, and HSP 70 were used for immunohistochemistry, and positive reactions were se miquantitatively analyzed. The presence of ischemic and postischemic l esions was ascertained with an antibody for microtubule-associated pro teins. Results After ischemia for 15 minutes and reperfusion, c-FOS wa s induced promptly after 1 to 6 hours in pyramidal cells of the CA3 an d CA4 regions, while c-JUN became visible in the same areas after reci rculation for 4 to 48 hours. HSP 70 was detected after recirculation f or 24 hours in the CA3 region. In layers I and II of the cerebral cort ex, c-FOS and c-JUN peaked at 3 hours and HSP 70 at 96 hours. Inductio n of these proteins was absent or negligible in the areas that develop ed ischemic or postischemic lesions, including the subiculum-CA1 and C A1 regions of the hippocampus and layers III/IV and Vb/VI of the cereb ral cortex. After shorter ischemia for 5 minutes and reperfusion, c-FO S and c-JUN were rapidly induced at 15 minutes to 1 hour except for th e subiculum-CA1 and CA1 regions of the hippocampus. Induction of HSP 7 0 did not occur for 24 hours and was noted only in the hippocampus. Co nclusions Induction of c-FOS and c-SUN occurred in the areas surviving after transient cerebral ischemia, but the extent of induction and th e latent period varied depending on the duration of the insult and the location. In the areas with ischemic or postischemic damage detected by loss of the reaction for microtubule-associated proteins, the induc tion of c-FOS and c-JUN was either absent or minimal, suggesting that active induction of those immediate early gene products occurred early in surviving neurons. On the other hand, the induction df HSP 70 did not occur until reperfusion for 24 hours and actively occurred only in the areas with earlier induction of c-FOS and/or c-JUN, suggesting th at the induction of HSP 70 occurred in neurons that survived to that p oint, but it did not participate in early responses for neuronal survi val after global cerebral ischemia.