Evelopment of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Previous studies by us and others confirmed that ROCKs inhibitors attenuated the symptoms and progression of experimental models of the abovementioned neurodegenerative diseases by inhibiting neuroinflammation, regulating immune imbalance, repairing the blood-brain barrier, and promoting nerve repair and myelin regeneration. Fasudil, the first ROCKs inhibitor to be used clinically, has a good therapeutic effect on neurodegenerative diseases. Fasudil increases the activity of neural stem cells and mesenchymal stem cells, thus optimizing cell therapy. This review will systematically describe, for the first time, the effects of abnormal activation of ROCKs on T cells, B cells, microglia, astrocytes, oligodendrocytes, and pericytes in neurodegenerative diseases of the central nervous system, summarize the therapeutic potential of fasudil in several experimental models of neurodegenerative diseases, and clarify the possible cellular and molecular mechanisms of ROCKs inhibition. This review also proposes that fasudil is a novel potential treatment, especially in combination with cell-based therapy. Findings from this review add support for further investigation of ROCKs and its inhibitor fasudil for the treatment of neurodegenerative diseases....

Background: Multiple sclerosis (MS) is marked by inflammatory demyelination in the central nervous system (CNS), involving diverse glial populations. This pathological process is associated with inflammation and oxidative stress. Proanthocyanidin B2 (PCB2), with its potent antioxidant properties, has been shown to alleviate demyelination in the cuprizone (CPZ) mouse model. It attenuates neuroinflammation and oxidative stress in both the cerebral microenvironment and astrocytes (AS). The xCT/GSH/GPX4 axis is a key regulatory pathway for oxidative stress. Therefore, we hypothesize that PCB2 can alleviate CPZ‐induced demyelination by regulating the xCT/GSH/GPX4 axis in AS. Methods: The study utilized forty C57BL/6 mice, randomly allocated into four groups of ten: a control group, a control group supplemented with PCB2 (60 mg/kg/day), a CPZ‐exposed group, and a CPZ‐exposed group supplemented with PCB2 (60 mg/kg/day). The control groups received a standard diet, whereas the CPZ groups were given the same diet supplemented with 0.2% CPZ for 6 weeks. From the fifth week onwards, the control and CPZ groups were administered physiological saline via intraperitoneal injection, whereas the PCB2‐supplemented groups received PCB2 for 2 weeks. Immunofluorescence staining, Western blot, and ELISA elucidated the cellular/molecular mechanisms of PCB2 targeting the xCT/GSH/GPX4 axis in AS to alleviate demyelination in vivo and in vitro. Results: In this study, PCB2 markedly regulated the xCT/GSH/GPX4 axis in AS, ameliorated the behavioral performance in CPZ mice, reduced inflammation, oxidative stress, lipid peroxidation, and the damage to oligodendrocytes (OLs), and inhibited demyelination. Conclusion: PCB2 can regulate the entire xCT/GSH/GPX4 axis of AS to reduce CPZ‐induced OL injury and demyelination, which may be a potentially effective drug for the treatment of multiple sclerosis.

The present study aimed to investigate the potential role and molecular mechanism of procyanidin B2 (PCB2) in the treatment of multiple sclerosis (MS), with the hope of providing novel strategies for the precision treatment of MS. The target genes of PCB2 and the disease-related target genes of MS were gathered from databases like GEO, GeneCards, OMIM, and DisGeNET. R language was employed for the identification of differentially expressed genes (DEGs), unsupervised clustering analysis, immune infiltration analysis, weighted gene co-expression network analysis (WGCNA), Gene Ontology (GO) analysis, and gene set enrichment analysis (GSEA). Eight machine learning algorithms were employed to screen key genes, and nomograms and ROC curves were constructed to assess the value of the screened biomarker genes in MS diagnosis. Through these analyses, four key genes closely associated with the pathogenesis of MS were selected, namely potassium ion channel subfamily H member 2 (KCNH2), prostaglandin-endoperoxide synthase 1 (PTGS1), estrogen receptor 1 (ESR1), and vascular endothelial growth factor A (VEGFA). These genes were significantly enriched in biological processes related to oxidative stress and served as potential targets for PCB2 in treating MS. Moreover, a key gene-transcription factor (TFs)-microRNA (miRNA) regulatory network was established to preliminarily explore the upstream regulatory mechanisms of these genes. Meanwhile, molecular docking and single-gene GSEA enrichment analysis were carried out to verify the interaction between PCB2 and these key genes. Finally, a CPZ (cuprizone)-induced mouse model of MS was set up, and the effects of PCB2 in MS treatment were verified by means of behavioral tests, pathological staining, immunofluorescence staining, ELISA, RT-PCR, and Western blot detection methods. PCB2 significantly improved behavioral performance in CPZ-induced MS mice, including enhanced motor coordination, reduced anxiety and hyperactivity, and improved spatial learning and memory. Additionally, PCB2 could promote myelin repair and decrease the levels of inflammatory response and oxidative stress in the mouse brain. Specifically, the expression levels of inflammatory factors such as TNF-α, IL-1β, and IL-6 decreased significantly, while the expression level of the anti-inflammatory factor IL-10 increased, and the activities of antioxidant enzymes like CAT, SOD, and GSH-Px increased notably. More importantly, PCB2 could upregulate the expression levels of the KCNH2, PTGS1, ESR1, and VEGFA genes and their related proteins, which may played significant roles in biological processes related to oxidative stress. This study disclosed the potential role of PCB2 in MS treatment by regulating the expression of key genes, providing a theoretical basis and potential therapeutic targets for personalized treatment of MS. PCB2 demonstrates good application prospects in MS treatment. Future research will further validate the clinical application value of these key genes and deeply explore the specific mechanism of PCB2 in MS treatment, aiming to develop more effective treatment regimens for MS.