Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death.
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.
Katchanov
J
J
Experimental Neurology, Department of Neurology, Institute of Pharmacology and Toxicology, Charité, Humboldt-University of Berlin, D-10098 Berlin, Germany.
Harms
C
C
Gertz
K
K
Hauck
L
L
Waeber
C
C
Hirt
L
L
Priller
J
J
von Harsdorf
R
R
Bruck
W
W
Hortnagl
H
H
Dirnagl
U
U
Bhide
P G
PG
Endres
M
M
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D001973:Bromodeoxyuridine; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007701:Kinetin; D051379:Mice; D008815:Mice, Inbred Strains; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D011687:Purines; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C090046:olomoucine; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; C495902:Cdk4 protein, mouse; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D001973:Bromodeoxyuridine; D005947:Glucose; D007701:Kinetin; D010100:Oxygen