Suppression of deltaPKC 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 (deltaPKC) is a kinase that has been strongly implicated in executing ischemic damage. We investigated the effects of hypothermia on deltaPKC 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 deltaPKC (CF-deltaPKC) increased after stroke. Both hypothermia (30 degrees C) and the caspase-3-specific inhibitor, Z-DQMD-FMK, blocked the accumulation of activated deltaPKC in the penumbra. Other hallmarks of deltaPKC 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-deltaPKC increases in the mitochondria and nuclei. Conversely, a specific deltaPKC activator, psideltaRACK, decreased the neuroprotective effect of hypothermia. Finally, deltaPKC activity may lead to mitochondrial injury and cytochrome c release, as the timing of cytochrome c release corresponded to the time course of deltaPKC translocation. Both cytochrome c release and deltaPKC translocation were blocked by hypothermia. In conclusion, hypothermia protects against ischemic damage in part by suppressing deltaPKC activation after stroke.
Shimohata
Takayoshi
T
Department of Neurosurgery, Stanford University, Stanford, California 94305-5327, USA.
Zhao
Heng
H
Sung
Jae Hoon
JH
Sun
Guohua
G
Mochly-Rosen
Daria
D
Steinberg
Gary K
GK
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D061945:Caspase Inhibitors; D002462:Cell Membrane / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D007035:Hypothermia; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007527:Isoenzymes; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D045304:Cytochromes c; D051745:Protein Kinase C-delta