title: Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination.
abstract: Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.
authors.affiliation: Department of Neurology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, 100071, China. lizhifang@sohu.com.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, 400038, China. heyangtaotmmu@163.com.
authors.forename: Yangtao
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Neurology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, 100071, China.
authors.forename: Shuangyi
authors.initials: S
authors.lastname: Fan
authors.affiliation: Department of Neurology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, 100071, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Sun
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002974:Clemastine / Q000008:administration & dosage*; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000150:complications / Q000473:pathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000150:complications / Q000473:pathology* / Q000517:prevention & control
chemical_list: D004676:Myelin Basic Protein; D003471:Cuprizone; D002974:Clemastine
keywords: Y-maze; antagonist; demyelination; differentiation; muscarinic; myelin basic protein; oligodendrocyte precursor; oligodendroglia; open-field