Effect of CSF1R Inhibitor on Glial Cells Population and Remyelination in The Cuprizone Model

Abstract

Multiple sclerosis is a kind of autoimmune and demyelinating disease and its pathological symptoms include inflammation, myelin loss, astrocytosis, and microgliosis. The colony stimulating factor 1 receptor (CSF1R), as an essential factor for the microglial function, and PLX3397 is its specific inhibitor. In this study, we assessed the effect of different doses of PLX3397 for microglial ablation on glial cells 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 chronic demyelination model induction. For microglial ablation, PLX3397 (290 mg/kg) was added to the animal food for 3, 7, 14 and 21 days. Glial cells number was measured using immunohistochemistry. We evaluated the rate of remyelination using electron microscopy and Luxol Fast Blue staining. The expression levels of all genes were assessed by qRT-PCR method. Data were analysed using Graph pad prism and SPSS software.Data showed that the administration of different doses of PLX3397 significantly (p˂0.001) reduced microglial cells. PLX3397 administration significantly (p˂0.001) increased oligodendrocytes population with along rise of the remyelination compared to the cuprizone mice, which was confirmed by the results of LFB and TEM. Gene results showed that PLX3397 treatment reduced CSF1R expression. According to results, the administration of PLX3397 for 21 days enhanced remyelination by increasing oligodendrocytes in the chronic demyelination model. These positive effects could be related to the reduction of microglia.

Colony‐stimulating factor‐1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model

“…Using two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene as a MS model, Groh et al (2019) showed that PLX3397, a potent inhibitor of CSF‐1R, attenuates neuroinflammation by reducing the number of resident microglia and attenuating T‐lymphocyte recruitment in the CNS, which leads to an amelioration of demyelination, axonopathic features and neuronal loss in the retinotectal system. Using chronic CPZ‐induced demyelination in mice, Tahmasebi et al (2019) and Tahmasebi et al (2021) have demonstrated that PLX3397 treatment induces an increase in the rate of myelination and a reduction in the rate of nerve fiber destruction and gap area between myelin layers, accompanied by motor recovery. More recently, using acute CPZ‐induced demyelination, Marzan et al (2021) have demonstrated that microglial depletion by PLX3397 administration greatly abrogates demyelination, OLG loss, and reactive astrocytosis.…”

Lanthionine Ketimine Ethyl Ester Accelerates Remyelination in a Mouse Model of Multiple Sclerosis

“…Phagocytosis of myelin debris (Cignarella et al, 2020; Ding et al, 2021; Shen et al, 2021) and production of protective factors (Aryanpour et al, 2021) can enhance remyelination, while production of inflammatory mediators can impede remyelination (Thomas & Pasquini, 2018). Microglial ablation using antagonists of the CSF1R show increased remyelination (Tahmasebi et al, 2021); as did astrocyte ablation using La-aminoadipate (Madadi et al, 2019). Reducing Ca 2+ influx into astrocytes has been shown to reduce both astrocyte and microglial activation, as well as promote remyelination (Zamora et al, 2020); suggesting that actions of LKE on voltage gated Ca 2+ channels could contribute to its actions.…”