Staurosporine, a novel protein kinase C inhibitor, prevents postischemic neuronal damage in the gerbil and rat.
The protective effects of protein kinase inhibitors and a calmodulin kinase inhibitor (W-7) against ischemic neuronal damage were examined in the CA1 subfield of the hippocampus. Staurosporine, KT5720, and KT5822 were used as inhibitors of protein kinase C (PKC), cyclic AMP-dependent protein kinase, and cyclic GMP-dependent protein kinase, respectively. All test compounds were injected topically into the CA1 subfield of the hippocampus. In the gerbil ischemia model, staurosporine (0.1-10 ng) administered 30 min before ischemia prevented neuronal damage in a dose-dependent manner. However, KT5720, KT5822, and W-7 were ineffective, even at a dose of 10 ng. In the rat ischemia model, staurosporine (10 ng) also prevented neuronal damage when administered before ischemic insult, although staurosporine administered 10 or 180 min after recirculation was ineffective. These results suggest the involvement of PKC in CA1 pyramidal cell death after ischemia and that the fate of vulnerable CA1 pyramidal cells through PKC-mediated processes could be determined during the early recirculation period.
Hara
H
H
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
Onodera
H
H
Yoshidomi
M
M
Matsuda
Y
Y
Kogure
K
K
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000473:pathology*; D002227:Carbazoles / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D005849:Gerbillinae; D006624:Hippocampus / Q000473:pathology*; D007211:Indoles; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D051381:Rats; D011920:Rats, Inbred WF; D019311:Staurosporine; D013449:Sulfonamides / Q000494:pharmacology
D000470:Alkaloids; D002227:Carbazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; C065336:KT 5822; C057416:KT 5720; C017967:W 7; D011493:Protein Kinase C; D019311:Staurosporine