EXPRESSION OF IMMEDIATE-EARLY GENE AND GROWTH-FACTOR MESSENGER-RNAS IN A FOCAL CEREBRAL-ISCHEMIA MODEL IN THE RAT

Background and Purpose: Increased release of excitatory neurotransmitt ers leading to activation of signal transduction has been noted after cerebral ischemia. One of the biochemical events in the signaling proc esses is an alteration of gene expression. A focal cerebral ischemia-r eperfusion model in the rat was used to study the postischemic alterat ion of selected proto-oncogene and neurotrophin gene expression. Metho ds: Focal ischemia in the cerebral cortex irrigated by the right middl e cerebral artery was induced by temporary occlusion of the right midd le cerebral artery and both common carotid arteries for 30 or 90 minut es. Expression of selected proto-oncogenes and neurotrophin genes was studied with Northern blot analysis and in situ hybridization. Results : Northern blot analysis showed that an increase in the expression of selected proto oncogenes including c-fos, c-jun, jun B, zif/268, and n ur 77 were noted 30 to 90 minutes into postischemic reperfusion. In si tu hybridization revealed different regional distribution of c-fos mRN A signal under different experimental conditions. Nuclear run-on exper iments showed that the increase in c-fos and jun B mRNA signals was du e to an increase in the transcription rate. An increase in AP-1 bindin g activity in the ischemic cortex was also noted. Increased expression of brain-derived neurotrophic factor and nerve growth factor mRNAs we re noted subsequent to the expression of immediate early genes in the ischemic cortex and adjacent areas in a biphasic pattern. Conclusions: Results are in agreement with the contention that increased c-fos and jun B expression leads to increased AP-1 binding activity, which in t urn has been linked to the enhanced expression of neurotrophin genes.