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Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death

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Item Type:Article
Title:Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death
Creators Name:Katchanov, J., Harms, C., Gertz, K., Hauck, L., Waeber, C., Hirt, L., Priller, J., von Harsdorf, R., Brueck, W., Hoertnagl, H., Dirnagl, U., Bhide, P.G. and Endres, M.
Abstract:After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16(INK4a) is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27(Kip1), another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen-glucose deprivation in vitro. The loss of Cdk inhibitors is followed by upregulation of cyclin D1, activation of Cdk2, and subsequent cytoskeletal disintegration. Most neurons undergo cell death before entering S-phase, albeit a small number ( approximately 1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell death in vitro. These results show that alteration of cell cycle regulatory mechanisms is a prelude to delayed neuronal death in focal cerebral ischemia and that pharmacological interventions aimed at neuroprotection may be usefully directed at cell cycle regulatory mechanisms.
Keywords:Cell Cycle, Cerebral Ischemia, Cyclin-Dependent Kinases, Delayed Neuronal Cell Death, Animals, Mice, Rats
Source:Journal of Neuroscience
ISSN:0270-6474
Publisher:Society for Neuroscience
Volume:21
Number:14
Page Range:5045-5053
Date:15 July 2001
Additional Information:Copyright (c) 2001 by The Society for Neuroscience
Official Publication:http://www.jneurosci.org/cgi/content/abstract/21/14/5045
PubMed:View item in PubMed

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