title: Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model.
abstract: The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZ-exposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice. Our results showed that CPZ administration up-regulated the expression of 16 cell cycle related genes, but down-regulated the expression of only one in the prefrontal cortex (PFC) of mice compared to control group. The treatment inhibited potential precursor cells exit from cell cycle. In the second experiment, we evaluated effects of a CDK inhibitor flavopiridol (FLA) on CPZ-induced neuropathological changes and spatial working memory impairment in mice.FLA treatment for one week effectively attenuated the CPZ-induced increases in NG2 positive cells, microglia and astrocytes, alleviated the concurrent mature oligodendrocyte loss and myelin breakdown, and improved spatial working memory deficit in the CPZ-exposed mice. These results suggest that CPZ-induced neuropathological changes involve in dysregulation of cell cycle related genes. The therapeutic effects of FLA on CPZ-exposed mice may be related to its ability of cell cycle inhibition.
authors: a Beijing Institute of Basic Medical Sciences , Haidian District, Beijing , China.
authors: Guiyun
authors: G
authors: Mi
authors: b The 89 Hospital of PLA , WeiFang City Shandong Province , China.
authors: Yunyun
authors: Y
authors: Gao
authors: a Beijing Institute of Basic Medical Sciences , Haidian District, Beijing , China.
authors: Shuai
authors: S
authors: Liu
authors: a Beijing Institute of Basic Medical Sciences , Haidian District, Beijing , China.
authors: Enmao
authors: E
authors: Ye
authors: a Beijing Institute of Basic Medical Sciences , Haidian District, Beijing , China.
authors: Yanyan
authors: Y
authors: Li
authors: a Beijing Institute of Basic Medical Sciences , Haidian District, Beijing , China.
authors: Xiao
authors: X
authors: Jin
authors: a Beijing Institute of Basic Medical Sciences , Haidian District, Beijing , China.
authors: Hongju
authors: H
authors: Yang
authors: a Beijing Institute of Basic Medical Sciences , Haidian District, Beijing , China.
authors: Zheng
authors: Z
authors: Yang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003471:Cuprizone; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy; D008570:Memory, Short-Term / Q000187:drug effects; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018797:Cell Cycle Proteins; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C077990:alvocidib; D003471:Cuprizone; D018844:Cyclin-Dependent Kinases
keywords: astrocyte; cell cycle; cognition; cuprizone; flavopiridol; microglia; oligodendrocyte