1. ¹Department of Neurosurgery, Stanford University, Stanford, California, USA
2. ²Department of Molecular Pharmacology, Stanford University, Stanford, California, USA
3. ³Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA
4. ⁴Stanford Stroke Center, Stanford University, Stanford, California, USA

Correspondence: Dr GK Steinberg, Department of Neurosurgery, Stanford University School of Medicine, 300 Pasteur Drive R200, Stanford, California 94305-5327, USA. E-mail: cerebral@stanford.edu

Received 30 August 2006; Revised 10 November 2006; Accepted 5 December 2006; Published online 7 February 2007.

Abstract

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 (PKC) is a kinase that has been strongly implicated in executing ischemic damage. We investigated the effects of hypothermia on 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 PKC (CF-PKC) increased after stroke. Both hypothermia (30°C) and the caspase-3-specific inhibitor, Z-DQMD-FMK, blocked the accumulation of activated PKC in the penumbra. Other hallmarks of 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-PKC increases in the mitochondria and nuclei. Conversely, a specific PKC activator, RACK, decreased the neuroprotective effect of hypothermia. Finally, PKC activity may lead to mitochondrial injury and cytochrome c release, as the timing of cytochrome c release corresponded to the time course of PKC translocation. Both cytochrome c release and PKC translocation were blocked by hypothermia. In conclusion, hypothermia protects against ischemic damage in part by suppressing PKC activation after stroke.