FOCAL ISCHEMIA CAUSES AN EXTENSIVE INDUCTION OF IMMEDIATE-EARLY GENESTHAT ARE SENSITIVE TO MK-801

Background and Purpose There is strong evidence to implicate glutamate in the cerebral damage caused by ischemia. In this study we investiga ted the role of glutamate receptors in mediating effects of middle cer ebral artery occlusion (MCAO) on immediate early gene expression in th e rat by quantitation of mRNA levels. Methods The effect of MCAO on th e induction of immediate early genes was studied in five regions, both ipsilateral and contralateral to the occlusion: the ''core'' ischemic area of the cortex in the central region of the middle cerebral arter y territory, the surrounding area, frontal cortex, occipital cortex, a nd hippocampus. Levels of c-fos, c-jun, zif-268, and krox-20 mRNA were measured by Northern and slot blot analysis. Results A large inductio n of c-fos mRNA was obtained in all four cortical regions ipsilateral to the occlusion, with the greatest effect detected in the core area. Little effect was detected in the ipsilateral hippocampus and in all c ontralateral regions. Pretreatment with MK-801 (3 mg/kg) largely inhib ited the induction of c-fos mRNA, indicating that the induction was me diated through an N-methyl-D-aspartate subtype of glutamate receptor. MCAO also produced a significant induction of c-jun and zif-268 mRNA i n ipsilateral cortical regions. Conclusions These results indicate tha t MCAO causes a profound modulation of the expression of multiple gene s in an extensive area of cerebral cortex extending beyond the immedia te area supplied by the middle cerebral artery. The marked effect of M K-801 indicates the potential importance of glutamate antagonists in r estricting the widespread deleterious effects of glutamate.