Center of Excellence, Arab Academy for Science and Technology and Maritime Transport, Alexandria, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini St, Cairo, 11562, Egypt.
Inflammation. 2021 Aug;44(4):1629-1642. doi: 10.1007/s10753-021-01447-6. Epub 2021 Mar 11.
Multiple sclerosis is a chronic inflammatory neurodegenerative disease of the central nervous system which injures the myelin sheath. Telmisartan and nifedipine are antihypertensive drugs that recently showed neuroprotective properties against neurodegenerative diseases. This study evaluated the neuroprotective effect of telmisartan or nifedipine in cuprizone-induced demyelination in mice by examining the underlying mechanisms. C57BL/6 mice received a diet containing 0.7% (w/w) cuprizone for 7 days followed by 3 weeks on a 0.2% cuprizone diet. Telmisartan (5 mg/kg/day, p.o.) or nifedipine (5 mg/kg/day, p.o.) was administered for 3 weeks starting from the second week. Telmisartan or nifedipine improved locomotor activity and enhanced motor coordination as demonstrated by open field, rotarod, and grip strength tests. Furthermore, telmisartan or nifedipine restored myelin basic protein mRNA and protein expression and increased luxol fast blue-staining intensity. Telmisartan or nifedipine attenuated cuprizone-induced oxidative stress and apoptosis by decreasing brain malondialdehyde and caspase-3 along with restoring reduced glutathione and brain-derived neurotrophic factor levels. Telmisartan or nifedipine exerted an anti-inflammatory effect by reducing the expression of nuclear factor kappa B (NF-κB p65) as well as pro-inflammatory cytokines and elevating the expression of IκB-α. In parallel, telmisartan or nifedipine upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the levels of heme oxygenase-1 and NADPH quinone oxidoreductase 1 enzymes. In conclusion, the current study provides evidence for the protective effect of telmisartan and nifedipine in cuprizone-induced demyelination and behavioral dysfunction in mice possibly by modulating NF-κB and Nrf2 signaling pathways.
多发性硬化症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。替米沙坦和硝苯地平是两种降压药物，最近它们在神经退行性疾病方面显示出了神经保护作用。本研究通过探究潜在机制，评估了替米沙坦或硝苯地平在铜诱导脱髓鞘小鼠模型中的神经保护作用。C57BL/6 小鼠接受含有 0.7%（w/w）铜的饮食 7 天，然后用含有 0.2%铜的饮食喂养 3 周。从第二周开始，替米沙坦（5 mg/kg/天，口服）或硝苯地平（5 mg/kg/天，口服）给药 3 周。替米沙坦或硝苯地平改善了运动活动能力，通过旷场实验、转棒实验和握力测试增强了运动协调性。此外，替米沙坦或硝苯地平恢复了髓鞘碱性蛋白 mRNA 和蛋白表达，并增加了卢索快速蓝染色强度。替米沙坦或硝苯地平通过降低脑丙二醛和半胱天冬酶-3，同时恢复还原型谷胱甘肽和脑源性神经营养因子水平，减轻了铜诱导的氧化应激和细胞凋亡。替米沙坦或硝苯地平通过降低核因子 kappa B（NF-κB p65）以及促炎细胞因子的表达，同时升高 IκB-α的表达，发挥了抗炎作用。此外，替米沙坦或硝苯地平上调了核因子红细胞 2 相关因子 2（Nrf2）的表达，增加了血红素加氧酶-1 和 NADPH 醌氧化还原酶 1 酶的水平。总之，本研究为替米沙坦和硝苯地平在铜诱导脱髓鞘和行为功能障碍小鼠模型中的保护作用提供了证据，这可能是通过调节 NF-κB 和 Nrf2 信号通路实现的。
