PMID- 11823715
DA - 20020201
IS - 0271-678X
VI - 22
IP - 2
DP - 2002 Feb
TI - Inhibition of Cyclin-Dependent Kinases Improves CA1 Neuronal Survival and Behavioral Performance After Global Ischemia in the Rat.
PG - 171-182 AB - SUMMARY: 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.
AD - Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario,
Canada; Basic Medical Sciences, Faculty of Medicine, Memorial University
of Newfoundland, St. John's, Newfoundland, Canada; and The Institute of
Medical Sciences and Department of Neurology, Tokai University School of
Medicine, Bohseidai, Isehara, Kanagawa, Japan.
AU - Wang F
AU - Corbett D
AU - Osuga H
AU - Osuga S
AU - Ikeda JE
AU - Slack RS
AU - Hogan MJ
AU - Hakim AM
AU - Park DS
LA - ENG
PT - JOURNAL ARTICLE
TA - J Cereb Blood Flow Metab
JC - HNL
JID - 8112566
EDAT- 2002/02/02 10:00
MHDA- 2002/02/02 10:00
PST - ppublish
SO - J Cereb Blood Flow Metab 2002 Feb;22(2):171-182.