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Media type:
E-Article
Title:
Mild Cerebral Ischemia Induces Loss of Cyclin-Dependent Kinase Inhibitors and Activation of Cell Cycle Machinery before Delayed Neuronal Cell Death
Published in:
The Journal of Neuroscience, 21 (2001) 14, Seite 5045-5053
Language:
English
DOI:
10.1523/jneurosci.21-14-05045.2001
ISSN:
0270-6474;
1529-2401
Origination:
Footnote:
Description:
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 p16INK4ais an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemiain vivo. Loss of p27Kip1, another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen–glucose deprivationin 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 (∼1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell deathin 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.