Inhibition of Cyclin-Dependent Kinases Improves CA1 Neuronal Survival and Behavioral Performance after Global Ischemia in the Rat

Fuhu Wang, Dale Corbett, Hitoshi Osuga, Sachiko Osuga, Joh-E Ikeda, Ruth S. Slack, Matthew J. Hogan, Antoine M. Hakim, David S. Park
2002 Journal of Cerebral Blood Flow and Metabolism  
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
more » ... ostreperfusion 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 cyclindependent kinase, was phosphorylated on a cyclin-dependent kinase consensus site after the global insult; this phosphoryla-tion was inhibited by flavopiridol administration. Importantly, flavopiridol had no effect on core body temperature, suggesting that the mechanism of neuroprotection was through cyclindependent 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.
doi:10.1097/00004647-200202000-00005 pmid:11823715 fatcat:2kec3mm2tvaodiltcme7ywr42i