Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat.
Increasing evidence suggests that cyclin-dependent kinases participate in neuronal death induced by multiple stresses in vitro. However, their role in cell death paradigms in vivo is not well characterized. Accordingly, the authors examined whether cyclin-dependent kinase inhibition resulted in functionally relevant and sustained neuroprotection in a model of global ischemia. Intracerebroventricular administration of the cyclin-dependent kinase inhibitor flavopiridol, immediately or at 4 hours postreperfusion after a global insult, reduced injury in the CA1 of the hippocampus when examined 7 days after reperfusion. No significant protection was observed when flavopiridol was administered 8 hours after reperfusion. The tumor-suppressor retinoblastoma protein, a substrate of cyclin-dependent kinase, was phosphorylated on a cyclin-dependent kinase consensus site after the global insult; this phosphorylation was inhibited by flavopiridol administration. Importantly, flavopiridol had no effect on core body temperature, suggesting that the mechanism of neuroprotection was through cyclin-dependent kinase inhibition but not through hypothermia. Furthermore, inhibition of cyclin-dependent kinases improved spatial learning behavior as assessed by the Morris water maze 7 to 9 days after reperfusion. However, the histologic protection observed at day 7 was absent 28 days after reperfusion. These results indicate that cyclin-dependent kinase inhibition provides an extended period of morphologic and functional neuroprotection that may allow time for other neuroprotective modalities to be introduced.
Wang
Fuhu
F
Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Corbett
Dale
D
Osuga
Hitoshi
H
Osuga
Sachiko
S
Ikeda
Joh-E
JE
Slack
Ruth S
RS
Hogan
Matthew J
MJ
Hakim
Antoine M
AM
Park
David S
DS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000503:physiopathology* / Q000523:psychology*; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016160:Retinoblastoma Protein / Q000378:metabolism; D013550:Swimming; D013997:Time Factors
D004791:Enzyme Inhibitors; D005419:Flavonoids; D018696:Neuroprotective Agents; D010880:Piperidines; D016160:Retinoblastoma Protein; C077990:alvocidib; D018844:Cyclin-Dependent Kinases