Effect of Notch1 gene on remyelination in multiple sclerosis in mouse models of acute demyelination

Abstract

This study aims to explore the effects of Notch1 gene on remyelination in multiple sclerosis (MS). A mouse model of acute demyelination was successfully established and the model mice were grouped as cuprizone (CPZ) group, CPZ + small interfering RNA (siRNA)-Notch1 (siNotch1) group, and CPZ + siRNA negative control (NC) group. Meanwhile, another 3 groups (control, control + siNotch1, and control + siRNA NC) were established in normal mice. The changes of weight and maintenance time in rotating drum of mice were observed. Western blot analysis for the protein expressions related to Notch signaling pathway and oligodendrocyte (OL) differentiation in the corpus callosum of the mice. After model establishment, the weight of CPZ-induced demyelinated mice was decreased. During the repair period, the balance ability and movement of the mice was recovered, especially for those injected with siNotch1 plasmid. After model establishment, the number of myelinated axons was decreased. In comparison with the CPZ and CPZ siRNA NC groups, the CPZ + siNotch1 group had a decrease in the number of premature OLs, but increase in mature OLs, and a decrease in oligodendrocyte precursor cells and astrocytes. The expressions of proteins related to Notch signaling pathway, such as HES, Jagged-1 were decreased in the CPZ + siNotch1 group in contrast to the CPZ and CPZ + siRNA groups, but the OL-related transcription factor Sox10 was increased in the CPZ + siNotch1 group than in the CPZ + siRNA NC and CPZ groups, and Id2 was decreased. Our study provided evidence that the inhibition of Notch1 gene could accelerate remyelination in MS.

The Notch pathway in CNS homeostasis and neurodegeneration

“…In the same model, it appears that astrocyte‐derived endothelin‐1 inhibits remyelination via a Jag1/Notch‐induced delay in oligodendrocyte differentiation; accordingly, pharmacological inhibition of endothelin signaling led to reduced Notch signaling, increased oligodendrocyte differentiation, and enhanced remyelination (Hammond et al, ). It was recently reported that Notch1 siRNA could improve “clinical” outcome in the cuprizone (CPZ) model of acute demyelination, by promoting remyelination accompanied by an increase in oligodendrocyte marker expression (Fan et al, ). Whether the role of Notch in remyelination represents a possible MS therapeutic target cannot be answered in the absence of human clinical data.…”

Bone Marrow Mesenchymal Stem Cells Promote Remyelination in Spinal Cord by Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnfα/Relb-Hes1 Pathway: A Rat Model Study of 2,5-Hexanedione-Induced Neurotoxicity

“…Hes1 is the main effector of Notch signaling pathway. It has been reported that Hes1 negatively regulates OPCs differentiation [19]. However, another study by Mathieu et al reported that Notch signaling activated by F3/contactin positively promoted OL mature in brain and neurosphere culture [20].…”

IL-9-triggered lncRNA Gm13568 regulates Notch1 in astrocytes through interaction with CBP/P300: contribute to the pathogenesis of experimental autoimmune encephalomyelitis

“…Emerging evidence indicates the Notch signal regulates the development and maturation of microglia, oligodendrocytes and CD4 + T cells in MS lesions, which are associated with MS pathology [34]. Inhibiting Notch1 pathway in oligodendrocytes improved remyelination in EAE mice and cuprizone (CPZ) demyelination model [34,35]. It is demonstrated that Notch-1 signaling is a critical regulator of intracerebral hemorrhage (ICH)-induced reactive astrogliosis [15].…”