Protein kinase C epsilon activation delays neuronal depolarization during cardiac arrest in the euthermic arctic ground squirrel.
During the pre-hibernation season, arctic ground squirrels (AGS) can tolerate 8 min of asphyxial cardiac arrest (CA) without detectable brain pathology. Better understanding of the mechanisms regulating innate ischemia tolerance in AGS has the potential to facilitate the development of novel prophylactic agents to induce ischemic tolerance in patients at risk of stroke or CA. We hypothesized that neuroprotection in AGS involves robust maintenance of ion homeostasis similar to anoxia-tolerant turtles. Ion homeostasis was assessed by monitoring ischemic depolarization (ID) in cerebral cortex during CA in vivo and during oxygen glucose deprivation in vitro in acutely prepared hippocampal slices. In both models, the onset of ID was significantly delayed in AGS compared with rats. The epsilon protein kinase C (epsilonPKC) is a key mediator of neuroprotection and inhibits both Na+/K+-ATPase and voltage-gated sodium channels, primary mediators of the collapse of ion homeostasis during ischemia. The selective peptide inhibitor of epsilonPKC (epsilonV1-2) shortened the time to ID in brain slices from AGS but not in rats despite evidence that epsilonV1-2 decreased activation of epsilonPKC in brain slices from both rats and AGS. These results support the hypothesis that epsilonPKC activation delays the collapse of ion homeostasis during ischemia in AGS.
Dave
Kunjan R
KR
Department of Neurology, Cerebral Vascular Disease Research Center, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida 33101, USA. KDave@med.miami.edu
Anthony Defazio
Richard
R
Raval
Ami P
AP
Dashkin
Oleksandr
O
Saul
Isabel
I
Iceman
Kimberly E
KE
Perez-Pinzon
Miguel A
MA
Drew
Kelly L
KL
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D019610:Cytoprotection / Q000502:physiology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006323:Heart Arrest / Q000150:complications*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D007477:Ions / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012589:Sciuridae / Q000502:physiology*; D015222:Sodium Channels / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D007477:Ions; D010455:Peptides; D015222:Sodium Channels; D051744:Protein Kinase C-epsilon; D000254:Sodium-Potassium-Exchanging ATPase