The levels of protein kinase C-gamma (PKC-gamma ) and the calcium/calmodulin-dependent kinase II-alpha (CaMKII-alpha) were measured in crude synaptosomal (P2), particulate (P3), and cytosolic (S3) fractions of the neocortex of rats exposed to 1-hour and 2-hour middle cerebral artery occlusion (MCAO) and 2-hour MCAO followed by 2-hour reperfusion. During MCAO, PKC levels increased in P2 and P3 in the most severe ischemic areas concomitantly with a decrease in S3. In the penumbra, PKCgamma decreased in S3 without any significant increases in P2 and P3. Total PKC-gamma also decreased in the penumbra but not in the ischemic core, suggesting that the protein is degraded by an energy-dependent mechanism, possibly by the 26S proteasome. The CaMKII-alpha levels increased in P2 but not P3 during ischemia and reperfusion in all ischemic regions, particularly in the ischemic core. Concomitantly, the levels in S3 decreased by 20% to 40% in the penumbra and by approximately 80% in the ischemic core. There were no changes in the total levels of CaMKII-alpha during MCAO. The authors conclude that during and after ischemia, PKC and CaMKII-alpha are translocated to the cell membranes, particularly synaptic membranes, where they may modulate cellular function, such as neurotransmission, and also affect cell survival. Drugs preventing PKC and/or CaMKII-alpha translocation may prove beneficial against ischemic cell death.