Activating deltaPKC antagonizes the protective effect of ERK1/2 inhibition against stroke in rats.
Two pathways that have been shown to mediate cerebral ischemic damage are the MEK/ERK cascade and the pro-apoptotic deltaPKC pathway. We investigated the relationship between these pathways in a rat model of focal ischemia by observing and modifying the activation state of each pathway. The ERK1/2 inhibitor, U0126, injected at ischemia onset, attenuated the increase in phosphorylated ERK1/2 (P-ERK1/2) after reperfusion. The deltaPKC inhibitor, deltaV1-1, delivered at reperfusion, did not significantly change P-ERK1/2 levels. In contrast, the deltaPKC activator, psi deltaRACK, injected at reperfusion, reduced ERK1/2 phosphorylation measured 4 h after reperfusion. Additionally, U0126 pretreatment at ischemia onset reduced infarct size compared with vehicle, but U0126 injected at the onset of reperfusion had no protection. Finally, combination of U0126 injection at ischemia onset plus deltaV1-1 injection at reperfusion further reduced infarct size, while combination of U0126 delivered at ischemia onset with psi deltaRACK injected at reperfusion increased infarct size compared with U0126 alone. In conclusion, we find that inhibiting both the MEK/ERK and the deltaPKC pathways offers greater protection than either alone, indicating they likely act independently.
Castañeda
Dora
D
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
Zhao
Heng
H
Mochly-Rosen
Daria
D
Steinberg
Gary K
GK
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D002070:Butadienes / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D002070:Butadienes; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009570:Nitriles; C113580:U 0126; D051745:Protein Kinase C-delta; D048052:Mitogen-Activated Protein Kinase 3