Clemastine (CLM) is repurposed to enhance remyelination in multiple sclerosis (MS) patients. CLM blocks histamine and muscarinic receptors as negative regulators to oligodendrocyte differentiation. These receptors are linked to the canonical and non-canonical Notch-1 signaling via specific ligands; Jagged-1 and F3/Contactin-1, respectively. Yet, there are no previous studies showing the influence of CLM on Notch entities. Herein, the study aimed to investigate to which extent CLM aligns to one of the two Notch-1 arms in experimental autoimmune encephalomyelitis (EAE) rat model. Three groups were utilized where first group received vehicles. The second group was injected by spinal cord homogenate mixed with complete Freund’s adjuvant on days 0 and 7. In the third group, CLM (5 mg/kg/day; p.o) was administered for 15 days starting from the day of the first immunization. CLM ameliorated EAE-associated motor and gripping impairment in rotarod, open-field, and grip strength arena beside sensory anomalies in hot plate, cold allodynia, and mechanical Randall-Selitto tests. Additionally, CLM alleviated depressive mood observed in tail suspension test. These findings harmonized with histopathological examinations of Luxol-fast blue stain together with enhanced immunostaining of myelin basic protein and oligodendrocyte lineage gene 2 in corpus callosum and spinal cord. Additionally, CLM enhanced oligodendrocyte myelination and maturation by increasing 2′,3′-cyclic nucleotide 3′-phosphodiesterase, proteolipid protein, aspartoacylase as well. CLM restored the level of F3/Contactin-1 in the diseased rats over Jagged-1 level; the ligand of the canonical pathway. This was accompanied by elevated gene expression of Deltex-1 and reduced hairy and enhancer-of-split homologs 1 and 5. Additionally, CLM suppressed microglial and astrocyte activation via reducing the expression of ionized calcium-binding adaptor molecule-1 as well as glial fibrillary acidic protein, respectively. These results outlined the remyelinating beneficence of CLM which could be due to augmenting the non-canonical Notch-1 signaling over the canonical one.

氯马斯汀 (CLM) 被重新用于增强多发性硬化症 (MS) 患者的髓鞘再生。 CLM 阻断组胺和毒蕈碱受体作为少突胶质细胞分化的负调节剂。这些受体通过特定配体与经典和非经典 Notch-1 信号传导相连；分别是 Jagged-1 和 F3/Contactin-1。然而，之前没有研究表明 CLM 对 Notch 实体的影响。在此，该研究旨在调查 CLM 在多大程度上与实验性自身免疫性脑脊髓炎 (EAE) 大鼠模型中的两个 Notch-1 臂之一对齐。使用了三组，第一组接收车辆。第二组在第0天和第7天注射与完全弗氏佐剂混合的脊髓匀浆。第三组从第一次免疫当天开始施用CLM（5mg/kg/天；po），持续15天。除了热板、冷异常性疼痛和机械 Randall-Selitto 测试中的感觉异常之外，CLM 还改善了旋转棒、开放场和握力场中与 EAE 相关的运动和握力障碍。此外，CLM 缓解了悬尾测试中观察到的抑郁情绪。这些发现与 Luxol 固蓝染色的组织病理学检查以及胼胝体和脊髓中髓磷脂碱性蛋白和少突胶质细胞谱系基因 2 的增强免疫染色相一致。此外，CLM还通过增加2',3'-环核苷酸3'-磷酸二酯酶、蛋白脂质蛋白、天冬氨酸酰化酶来增强少突胶质细胞髓鞘形成和成熟。 CLM使患病大鼠的F3/Contactin-1水平恢复到高于Jagged-1水平；经典途径的配体。这伴随着 Deltex-1 基因表达的升高以及毛状和分裂增强子同源物 1 和 5 的减少。 此外，CLM 通过分别减少离子钙结合接头分子 1 和神经胶质纤维酸性蛋白的表达来抑制小胶质细胞和星形胶质细胞的活化。这些结果概述了 CLM 的髓鞘再生益处，这可能是由于非规范 Notch-1 信号传导比规范信号增强。