Department of Pharmacology and Toxicology, Faculty of Pharmacy, Assiut University, Asyût, 71526, Egypt.
Department of Anatomy and Histology, School of Veterinary Medicine, Badr University in Assiut, New Nasser City, West of Assiut, Asyût, Egypt.
Inflammopharmacology. 2024 Apr;32(2):1295-1315. doi: 10.1007/s10787-024-01442-x. Epub 2024 Mar 21.
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system that injures the myelin sheath, provoking progressive axonal degeneration and functional impairments. No efficient therapy is available at present to combat such insults, and hence, novel safe and effective alternatives for MS therapy are extremely required. Rutin (RUT) is a flavonoid that exhibits antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. The present study evaluated the potential beneficial effects of two doses of RUT in a model of pattern-III lesion of MS, in comparison to the conventional standard drug; dimethyl fumarate (DMF). Demyelination was induced in in male adult C57BL/6 mice by dietary 0.2% (w/w) cuprizone (CPZ) feeding for 6 consecutive weeks. Treated groups received either oral RUT (50 or 100 mg/kg) or DMF (15 mg/kg), along with CPZ feeding, for 6 consecutive weeks. Mice were then tested for behavioral changes, followed by biochemical analyses and histological examinations of the corpus callosum (CC). Results revealed that CPZ caused motor dysfunction, demyelination, and glial activation in demyelinated lesions, as well as significant oxidative stress, and proinflammatory cytokine elevation. Six weeks of RUT treatment significantly improved locomotor activity and motor coordination. Moreover, RUT considerably improved remyelination in the CC of CPZ + RUT-treated mice, as revealed by luxol fast blue staining and transmission electron microscopy. Rutin also significantly attenuated CPZ-induced oxidative stress and inflammation in the CC of tested animals. The effect of RUT100 was obviously more marked than either that of DMF, regarding most of the tested parameters, or even its smaller tested dose. In silico docking revealed that RUT binds tightly within NF-κB at the binding site of the protein-DNA complex, with a good negative score of -6.79 kcal/mol. Also, RUT-Kelch-like ECH-associated protein 1 (Keap1) model clarifies the possible inhibition of Keap1-Nrf2 protein-protein interaction. Findings of the current study provide evidence for the protective effect of RUT in CPZ-induced demyelination and behavioral dysfunction in mice, possibly by modulating NF-κB and Nrf2 signaling pathways. The present study may be one of the first to indicate a pro-remyelinating effect for RUT, which might represent a potential additive benefit in treating MS.
多发性硬化症（MS）是一种中枢神经系统的慢性炎症性神经退行性疾病，会损伤髓鞘，引发进行性轴突变性和功能障碍。目前尚无有效的治疗方法来对抗这种损伤，因此，非常需要寻找治疗多发性硬化症的新型安全有效的替代方法。芦丁（RUT）是一种类黄酮，在多种脑损伤中具有抗氧化、抗炎和神经保护作用。本研究评估了两种剂量的 RUT 在多发性硬化症 III 型病变模型中的潜在有益作用，并与传统标准药物富马酸二甲酯（DMF）进行了比较。通过连续 6 周的饮食 0.2%（w/w）铜锌螯合物（CPZ）喂养，诱导雄性成年 C57BL/6 小鼠脱髓鞘。治疗组在连续 6 周的 CPZ 喂养期间，分别接受口服 RUT（50 或 100mg/kg）或 DMF（15mg/kg）治疗。然后，对小鼠进行行为变化测试，随后对胼胝体（CC）进行生化分析和组织学检查。结果表明，CPZ 导致脱髓鞘病变中的运动功能障碍、脱髓鞘和神经胶质激活，以及显著的氧化应激和促炎细胞因子升高。6 周的 RUT 治疗显著改善了运动活动和运动协调。此外，RUT 可显著改善 CPZ+RUT 治疗组小鼠 CC 中的髓鞘再生，如卢索快速蓝染色和透射电子显微镜所示。芦丁还显著减轻了 CPZ 诱导的测试动物 CC 中的氧化应激和炎症。与大多数测试参数甚至其较小的测试剂量相比，RUT100 的作用更为明显。基于结构的对接显示，RUT 与 NF-κB 紧密结合，位于蛋白质-DNA 复合物的结合位点，具有良好的负评分-6.79kcal/mol。此外，RUT-Kelch 样 ECH 相关蛋白 1（Keap1）模型阐明了 Keap1-Nrf2 蛋白-蛋白相互作用可能被抑制。本研究为 RUT 在 CPZ 诱导的脱髓鞘和小鼠行为功能障碍中的保护作用提供了证据，这可能是通过调节 NF-κB 和 Nrf2 信号通路来实现的。本研究可能是首次表明 RUT 具有促髓鞘形成作用的研究之一，这可能在治疗多发性硬化症方面具有潜在的附加益处。
