Article: article from journal or magazin.
Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death
Journal of Neuroscience
Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. --- Old month value: Jul 15
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.
Animals Brain Ischemia/*metabolism/pathology Bromodeoxyuridine *CDC2-CDC28 Kinases Cell Cycle/physiology *Cell Cycle Proteins Cell Death Cell Hypoxia Cells, Cultured Cyclin D1/metabolism Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor p16/deficiency/*metabolism Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases/*antagonists & inhibitors/metabolism Disease Models, Animal Enzyme Inhibitors/pharmacology Glucose/deficiency/metabolism In Situ Nick-End Labeling Kinetin Mice Mice, Inbred Strains Microtubule-Associated Proteins/deficiency/*metabolism Neurons/*metabolism/pathology Oxygen/metabolism Protein-Serine-Threonine Kinases/metabolism *Proto-Oncogene Proteins Purines/pharmacology Rats Rats, Wistar *Tumor Suppressor Proteins
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