Background and purpose: Increased release of excitatory neurotransmitters leading to activation of signal transduction has been noted after cerebral ischemia. One of the biochemical events in the signaling processes is an alteration of gene expression. A focal cerebral ischemia-reperfusion model in the rat was used to study the postischemic alteration of selected proto-oncogene and neurotrophin gene expression.
Methods: Focal ischemia in the cerebral cortex irrigated by the right middle cerebral artery was induced by temporary occlusion of the right middle cerebral artery and both common carotid arteries for 30 or 90 minutes. 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 nur 77 were noted 30 to 90 minutes into postischemic reperfusion. In situ hybridization revealed different regional distribution of c-fos mRNA signal under different experimental conditions. Nuclear run-on experiments showed that the increase in c-fos and jun B mRNA signals was due to an increase in the transcription rate. An increase in AP-1 binding activity in the ischemic cortex was also noted. Increased expression of brain-derived neurotrophic factor and nerve growth factor mRNAs were 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 turn has been linked to the enhanced expression of neurotrophin genes.