Suppression of δPKC activation after focal cerebral ischemia contributes to the protective effect of hypothermia

Mild hypothermia is a robust neuroprotective treatment for stroke. Understanding the mechanisms underlying hypothermia's benefits will lead to more effective treatments to prevent stroke damage. Delta protein kinase C (delta PKC) is a kinase that has been strongly implicated in executing ischemic damage. We investigated the effects of hypothermia on delta PKC activation, as determined by its subcellular translocation, proteolytic cleavage, and phosphorylation in a focal cerebral ischemia model. The amount of constitutively activated C-terminal catalytic fragment of delta PKC (CF-delta PKC) increased after stroke. Both hypothermia (30 degrees C) and the caspase-3-specific inhibitor, Z-DQMD-FMK, blocked the accumulation of activated delta PKC in the penumbra. Other hallmarks of delta PKC activation, its translocation to the mitochondria, and nucleus were observed in the penumbra as early as 10 mins after reperfusion. These events were blocked by hypothermia. Hypothermia also blocked CF-delta PKC increases in the mitochondria and nuclei. Conversely, a specific delta PKC activator, psi delta RACK, decreased the neuroprotective effect of hypothermia. Finally, delta PKC activity may lead to mitochondrial injury and cytochrome c release, as the timing of cytochrome c release corresponded to the time course of delta PKC translocation. Both cytochrome c release and delta PKC translocation were blocked by hypothermia. In conclusion, hypothermia protects against ischemic damage in part by suppressing delta PKC activation after stroke.