Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination  

作　　者：Zhifang Li Yangtao He Shuangyi Fan Binbin Sun 

机构地区：[1]Department of Neurology, Affi liated Hospital of Academy of Military Medical Sciences [2]Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University

出　　处：《Neuroscience Bulletin》2015年第5期617-625,共9页神经科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China ( 81100897 and 81100926 );the Natural Science Foundation of Chongqing Municipality, China (cstc2011jj A0856)

摘　　要：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 for3 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.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 for3 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.

关 键 词：demyelination myelin basic protein muscarinic open-field Y-maze antagonist differentiation oligodendroglia oligodendrocyte precursor 

分 类 号：R744.5[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]