Rat focal cerebral ischemia induced astrocyte proliferation and delayed neuronal death are attenuated by cyclin-dependent kinase inhibition.
Astroglial proliferation and delayed neuronal death are two common pathological processes in the ischemic brain. However, it is not clear if astrogliosis causes delayed neuronal death. In this study, we addressed this potential linkage by examining the relationship between attenuated astrocyte proliferation, induced by cyclin-dependent kinase (CDK) inhibition, and delayed neuronal death in rat ischemic hippocampus. Our results show that following middle cerebral artery occlusion (MCAO), astrocyte hypertrophy and proliferation were closely associated with delayed neuronal death. Importantly, administration of olomoucine, a selective CDK inhibitor, not only suppressed astroglial proliferation and glial scar formation, but also decreased neuronal cell death in the ischemic boundary zone and hippocampal CA1 region at days 1 and 30 after MCAO. These results indicate that reactive astrogliosis and delayed neuronal death, at least in rat hippocampus, are sequential pathological events following MCAO. Therefore, suppressing astroglial cell cycle progression in acute focal cerebral ischemia may be beneficial to neuronal survival. Our study also implies that cell cycle regulation should be considered as a promising future therapeutic intervention in treating those neurological diseases characterized by an excessive astrocyte proliferation.
Wang
Wei
W
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China. wwang@tjh.tjmu.edu.cn
Redecker
Christoph
C
Yu
Zhi-Yuan
ZY
Xie
Min-Jie
MJ
Tian
Dai-Shi
DS
Zhang
Liang
L
Bu
Bi-Tao
BT
Witte
Otto W
OW
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D007701:Kinetin / Q000008:administration & dosage*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; C090046:olomoucine; D010751:Phosphopyruvate Hydratase; D007701:Kinetin