SPECIFIC INDUCTION OF PROTEIN-KINASE C-DELTA SUBSPECIES AFTER TRANSIENT MIDDLE CEREBRAL-ARTERY OCCLUSION IN THE RAT-BRAIN - INHIBITION BY MK-801

Protein kinase C (PKC) consists of a family of closely related Ca2+/ph ospholipid-dependent phosphotransferase isozymes, most of which are pr esent in the brain and are differentially activated by second messenge rs. Calcium-dependent PKC activity may cause neuronal degeneration aft er ischemic insult. PKC is also involved in trophic-factor signaling, indicating that activity of some PKC subspecies may be beneficial to t he injured brain. Therefore, we screened long-term changes in the expr ession of multiple PKC subspecies after focal brain ischemia. Middle c erebral artery occlusion was produced by using an intraluminal suture for 30 min or 90 min. In in situ hybridization experiments, mRNA level s of PKC alpha, -beta, -gamma, -delta, -epsilon and -zeta were decreas ed in the infarct core 4 hr after ischemia and were lost completely 12 hr after ischemia. In areas surrounding the core, PKC delta mRNA was specifically induced 4, 12, and 24 hr after ischemia in the cortex. At 3 and 7 d, the core and a rim around it showed increased mRNA levels of PKC delta. No other subspecies were induced. At 2 d, immunoblotting demonstrated increased levels of PKC delta protein in the perifocal t issue, and immunocytochemistry revealed an increased number of PKC del ta-positive neurons in the perifocal cortex. In the core, PKC delta-po sitive macrophages and endothelial cells were seen. Pretreatment with MK-801, an NMDA antagonist, inhibited cortical PKC delta mRNA inductio n. The data show that focal brain ischemia induces PKC delta mRNA and protein but not other PKC subspecies through the activation of NMDA re ceptors and that the upregulation lasts for several days in neurons of the perifocal zone.