Differential Expression of miRNAs and Behavioral Change in the Cuprizone-Induced Demyelination Mouse Model.

Han Han,Song Song,Kang Kang,Jeon Jeon,Yoo Yoo,Park Park,Lee Lee,Min Min

doi:10.3390/ijms21020646

Abstract

The demyelinating diseases of the central nervous system involve myelin abnormalities, oligodendrocyte damage, and consequent glia activation. Neurotoxicant cuprizone (CPZ) was used to establish a mouse model of demyelination. However, the effects of CPZ on microRNA (miRNA) expression and behavior have not been clearly reported. We analyzed the behavior of mice administered a diet containing 0.2% CPZ for 6 weeks, followed by 6 weeks of recovery. Rotarod analysis demonstrated that the treated group had poorer motor coordination than control animals. This effect was reversed after 6 weeks of CPZ withdrawal. Open-field tests showed that CPZ-treated mice exhibited significantly increased anxiety and decreased exploratory behavior. CPZ-induced demyelination was observed to be alleviated after 4 weeks of CPZ treatment, according to luxol fast blue (LFB) staining and myelin basic protein (MBP) expression. miRNA expression profiling showed that the expression of 240 miRNAs was significantly changed in CPZ-fed mice compared with controls. Furthermore, miR-155-5p and miR-20a-5p upregulations enhanced NgR induction through Smad 2 and Smad 4 suppression in demyelination. Taken together, our results demonstrate that CPZ-mediated demyelination induces behavioral deficits with apparent alterations in miRNA expression, suggesting that differences in miRNA expression in vivo may be new potential therapeutic targets for remyelination.

Highlights

Demyelination of the central nervous system (CNS) is a typical feature of diseases such as multiple sclerosis (MS) and contributes to axon injury and cerebral atrophy, which are characteristic of late stages of the disease [1,2]
After 6 weeks of treatment, despite an overall increase in weight, CPZ-fed mice weighed significantly less than control mice (Figure 1B; p < 0.01)
At the end of the recovery period with normal chow, the treated animals had an overall increase in body weight of 27.27% with respect to the initial weight, while the weight of the control animals increased by 28.5%

Summary

Introduction

Demyelination of the central nervous system (CNS) is a typical feature of diseases such as multiple sclerosis (MS) and contributes to axon injury and cerebral atrophy, which are characteristic of late stages of the disease [1,2]. MS lesions are pathologically divided into four distinct patterns (I–IV) based on complement activation, IgG deposition, and loss of myelin-associated glycoproteins [3,4]. The challenges of MS research are analyzing the causes of remyelination failure and developing methods to restore myelin. The research includes using animal models to help understand the demyelination and remyelination mechanisms, facilitating the study of cellular responses taking place in this process, and providing a robust platform for elucidating putative therapeutic targets. There is the limitation that no current animal model faithfully replicates the myriad of symptoms seen in the clinical condition of MS [2,7]

Methods

Results

Conclusion