Effect of CSF1R inhibitor on glial cells population and remyelination in the cuprizone model

Fatemeh Tahmasebi,Iraj Ragerdi Kashani,Shirin Barati

doi:10.1016/j.npep.2021.102179

Abstract

Multiple sclerosis is a kind of autoimmune and demyelinating disease with pathological symptoms such as inflammation, myelin loss, astrocytosis, and microgliosis. The colony stimulating factor 1 receptor (CSF1R) is an essential factor for the microglial function, and PLX3397 (PLX) is its specific inhibitor. In this wstudy, we assessed the effect of different doses of PLX for microglial ablation on glial cell population and remyelination process. Sixty male C57BL/6 mice (8 weeks old) were divided into 6 groups. The animals were fed with 0.2% cuprizone diet for 12 weeks. For microglial ablation, PLX (290 mg/kg) was added to the animal food for 3, 7, 14 and 21 days. Glial cell population was measured using immunohistochemistry. The rate of remyelination was evaluated using electron microscopy and Luxol Fast Blue staining. The expression levels of all genes were assessed by qRT-PCR method. Data were analysed using GraphPad Prism and SPSS software. The results showed that the administration of different doses of PLX significantly reduced microglial cells (p ≤ .001). PLX administration also significantly increased oligodendrocytes population (p ≤ .001) and remyelination compared to the cuprizone mice, which was aligned with the results of LFB and TEM. Gene results showed that PLX treatment reduced CSF1R expression. According to the results, the administration of PLX for 21 days enhanced remyelination by increasing oligodendrocytes in the chronic demyelination model. These positive effects could be related to the reduction of microglia.

Highlights

Multiple sclerosis (MS) is a kind of autoimmune disease characterized with multifocal lesions in the central nervous system (CNS), which affect almost 2.5 million people worldwide (Goldmann and Prinz 2013)
The messenger RNA (mRNA) levels revealed that the administration of PLX3397, as the colony stimulating factor 1 receptor (CSF1R) inhibitor, with varying periods such as [3, 7, 14] and 21 days significantly (p≤.001) reduced the gene expression of CSF1R compared to the cuprizone group
The PLX3397 treatment for 21 days was more effective in terms of microglial ablation, so that more than 95% of the microglia were removed after 21 days (Fig. 1A)

Summary

Introduction

Multiple sclerosis (MS) is a kind of autoimmune disease characterized with multifocal lesions in the central nervous system (CNS), which affect almost 2.5 million people worldwide (Goldmann and Prinz 2013). It is a chronic, neurodegenerative disorder and its pathological symptoms consist of inflammation, myelin damage and axonal injury, astrocytosis, and microgliosis (Kramann et al 2016). As CNS resident innate immune cells, respond to inflammation by the secretion of inflammatory cytokines that exacerbate disease symptoms As such, they play a vital role in both healthy and pathological conditions (Nimmerjahn, Kirchhoff, and Helmchen 2005). Some studies suggest that axonal degeneration in diseases such as MS is a result of inflammation and chronic demyelination (Bjartmar et al 2000; Dutta et al 2006)

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Discussion

Conclusion