PKCγ and PKCε Are Differentially Activated and Modulate Neurotoxic Signaling Pathways During Oxygen Glucose Deprivation in Rat Cortical Slices

Cerebral ischemia is known to trigger a series of intracellular events such as changes in metabolism, membrane function and intracellular transduction, which eventually leads to cell death. Many of these processes are mediated by intracellular signaling cascades that involve protein kinase activation. Among all the kinases activated, the serine/threonine kinase family, protein kinase C (PKC), particularly, has been implicated in mediating cellular response to cerebral ischemic and reperfusion injury. In this study, using oxygen-glucose deprivation (OGD) in acute cortical slices as an in vitro model of cerebral ischemia, I show that PKC family of isozymes, specifically PKCγ and PKCε are differentially activated during OGD. Detecting the expression and activation levels of these isozymes in response to different durations of OGD insult revealed an early activation of PKCε and delayed activation of PKCγ, signifying their roles in response to different durations and stages of ischemic stress. Specific inhibition of PKCγ and PKCε significantly attenuated OGD induced cytotoxicity, rise in intracellular calcium, membrane depolarization and reactive oxygen species formation, thereby enhancing neuronal viability. This study clearly suggests that PKC family of isozymes; specifically PKCγ and PKCε are involved in OGD induced intracellular responses which lead to neuronal death. Thus isozyme specific modulation of PKC activity may serve as a promising therapeutic route for the treatment of acute cerebral ischemic injury.