Activating δPKC antagonizes the protective effect of ERK1/2 inhibition against stroke in rats

Two pathways that have been shown to mediate cerebral ischemic damage are the MEK/ERK cascade and the pro-apoptotic delta PKC pathway. We investigated the relationship between these pathways in a rat model of focal ischemia by observing and modifying the activation state of each pathway. The ERK1/2 inhibitor, U0126, injected at ischemia onset, attenuated the increase in phosphorylated ERK1/2 (P-ERK1/2) after reperfusion. The delta PKC inhibitor, delta V1-1, delivered at reperfusion, did not significantly change P-ERKl/2 levels. In contrast, the delta PKC activator, psi delta RACK, injected at reperfusion, reduced ERKl/2 phosphorylation measured 4 h after reperfusion. Additionally, U0126 pretreatment at ischemia onset reduced infarct size compared with vehicle, but U0126 injected at the onset of reperfusion had no protection. Finally, combination of U0126 injection at ischemia onset plus delta V1-1 injection at reperfusion further reduced infarct size, while combination of U0126 delivered at ischemia onset with psi delta RACK injected at reperfusion increased infarct size compared with U0126 alone. In conclusion, we find that inhibiting both the MEK/ERK and the delta PKC pathways offers greater protection than either alone, indicating they likely act independently. (c) 2008 Elsevier B.V. All rights reserved.