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 fi eld 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 fi ndings indicate that enhancing remyelination may be a potential therapy for schizophrenia.

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

“…Preclinical work validated the efficacy of clemastine fumarate in vitro and in animal models. 17,19 Additional work confirmed the efficacy of clemastine fumarate in multiple animal models [17][18][19][20][21][22] and showed that this benefit was mediated specifically via remyelination induced from oligo dendrocyte differentiation and not via effects on the immune system. 19 We furthermore showed the capacity of clemastine fumarate to induce oligodendrocyte progenitor cell (OPC) differentiation and myelination with human OPCs (appendix).…”

“…Preclinical data unequivocally showed that clemastine fumarate promotes oligodendrocyte precursor differentiation 17,18 and remyelination [19][20][21][22] without modulating the immune system. 19 The robustness of the findings were documented by the latency improvement observed in both groups of the cohort while on active treatment.…”

Cholinergic signaling in myelination

“…Non‐selective muscarinic receptor antagonists promote myelin repair in rodents (Deshmukh et al, ; Mei et al, ). Clemastine, an antimuscarinic compound, rescues behavioral changes and enhances remyelination in a cuprizone mouse model of demyelination (Li et al, ). In these studies, the behaviors analyzed were open field tests and Y‐maze learning, which are considered assays of schizophrenia‐like behaviors.…”

“…In these studies, the behaviors analyzed were open field tests and Y‐maze learning, which are considered assays of schizophrenia‐like behaviors. Clemastine also enhances myelination in the prefrontal cortex and rescues behavioral changes observed in socially isolated mice (Li et al, ; Liu et al, ). Sexual dimorphism is evident in oligodendrocyte development, myelination, and risk for multiple sclerosis (Swamydas, et al, ).…”

A novel myelin protein zero transgenic zebrafish designed for rapid readout of in vivo myelination

“…Therefore, identifying small molecule therapies that specifically promote oligodendrocyte differentiation and myelin production is important for the repair process, with the goal of slowing the degeneration of demyelinated axons (Bjartmar & Trapp, 2001). For example, two separate high throughput screens of FDA approved libraries using cultured OPCs independently identified Clemastine, an antihistamine that enhances oligodendrocyte differentiation and myelination in rodents (Li, He, Fan, & Sun, 2015;J. For example, two separate high throughput screens of FDA approved libraries using cultured OPCs independently identified Clemastine, an antihistamine that enhances oligodendrocyte differentiation and myelination in rodents (Li, He, Fan, & Sun, 2015;J.…”