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Previous Article | Next Article
The Journal of Neuroscience, July 15, 2001, 21(14):5045-5053
Mild Cerebral Ischemia Induces Loss of Cyclin-Dependent Kinase Inhibitors and Activation of Cell Cycle Machinery before Delayed Neuronal Cell Death
Juri Katchanov1, Christoph Harms1, 2, Karen Gertz1, Ludger Hauck3, Christian Waeber4, Lorenz Hirt4, Josef Priller1, Rüdiger von Harsdorf3, Wolfgang Brück6, Heide Hörtnagl2, Ulrich Dirnagl1, Pradeep G. Bhide5, and Matthias Endres1 1 Experimental Neurology, Department of Neurology, and 2 Institute of Pharmacology and Toxicology, Charité, Humboldt-University of Berlin, D-10098 Berlin, Germany, 3 Max-Delbrück-Center für Molecular Medicine and Franz Volhard Clinic, D-13125 Berlin, Germany, 4 Stroke and Neurovascular Regulation Laboratory, and 5 Developmental Neurobiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 Massachusetts, and 6 Department of Neuropathology, Charité, Virchow Hospital, Humboldt-University of Berlin, D-13353 Berlin, Germany
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 p16INK4a is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27Kip1, 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 (~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.
Key words: cell cycle; cerebral ischemia; cyclin-dependent kinases; delayed neuronal cell death; p16 INK4a; p27Kip1
Copyright © 2001 Society for Neuroscience 0270-6474/01/21145045-09$05.00/0
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