Study of neuroprotective effect of ZJU-37 in a Multiple Sclerosis Demyelination Model

Objective To investigate the neuroprotective effect of ZJU-37, a novel Receptor-interacting protein kinase 1 (RIPK1) inhibitor, in an experimental mouse model of multiple sclerosis (MS).Methods The dataset GSE172497 was obtained from the GEO database, and differential expression analysis along with pathway enrichment analysis between the ZJU-37 treatment group and the control group in oligodendrocyte precursor cells (OPCs) were performed using R. For the animal study, an MS mouse model was established by Cuprizone induction. Mice were randomly divided into three groups: the Control group (standard diet), the Cuprizone model group (0.2% Cuprizone diet + daily solvent injection), and the ZJU-37 intervention group (Cuprizone diet + daily intraperitoneal injection of ZJU-37 at 10 mg/kg). After 6 weeks of intervention, brain tissues were collected. Myelin staining and transmission electron microscopy (TEM) were used to evaluate the degree of demyelination and ultrastructural changes, respectively. Immunohistochemistry and Western blot were performed to detect the expression level of p-RIPK1 protein.Results Bioinformatics analysis suggested that ZJU-37 could regulate signaling pathways related to the cell cycle and DNA repair in OPCs. Animal experiments showed that compared with the Cuprizone model group, ZJU-37 intervention significantly reduced the area of demyelination in the corpus callosum, improved myelin ultrastructure (P < 0.001), increased the proportion of myelinated axons and maintained myelin thickness (P < 0.0001), while markedly decreasing the number of p-RIPK1-positive cells (P < 0.0001) and the protein expression level of p-RIPK1.Conclusion ZJU-37 can down-regulate the expression of p-RIPK1 in the brain tissue of MS mice, alleviate myelin damage, and enhance neuroprotection. This effect may be related to its promotion of oligodendrocyte precursor cell (OPC) proliferation.