Neuroprotective Effects of Telmisartan and Nifedipine Against Cuprizone-Induced Demyelination and Behavioral Dysfunction in Mice: Roles of NF-κB and Nrf2
Neuroprotective Effects of Telmisartan and Nifedipine Against Cuprizone-Induced Demyelination and Behavioral Dysfunction in Mice: Roles of NF-κB and Nrf2
复制标题
DOI：
10.1007/s10753-021-01447-6
复制
发表时间：
2021-03-11
期刊：
影响因子：
5.1
通讯作者：
El Sayed, Nesrine S.
中科院分区：
文献类型：
--
作者：
Abd El Aziz, Amira E.;Sayed, Rabab Hamed;El Sayed, Nesrine S.
多发性硬化症是一种慢性炎症性神经退行性疾病，损害髓鞘。替米沙坦和硝苯地平是最近显示出对神经退行性疾病具有神经保护作用的抗高血压药物。本研究通过研究替米沙坦或硝苯地平的神经保护机制，评价替米沙坦或硝苯地平对铜酮诱导的小鼠脱髓鞘的神经保护作用。C57BL/6小鼠饲喂含0.7%(w/w)铜试剂的饲料，连续7天，然后用0.2%的铜试剂饲料喂养3周。替米沙坦(5 mg/kg/d，P.O.)或硝苯地平(5 mg/kg/d，P.O.)从第二周开始给药3周。替米沙坦或硝苯地平改善运动活动和增强运动协调性，如开阔场地、旋转和握力测试所证明的那样。此外，替米沙坦或硝苯地平可恢复髓鞘碱性蛋白mRNA和蛋白的表达，并增加豪华坚固蓝染色强度。替米沙坦或硝苯地平通过降低脑组织丙二醛和caspase-3以及恢复降低的谷胱甘肽和脑源性神经营养因子水平来减轻铜宗诱导的氧化应激和细胞凋亡。替米沙坦或硝苯地平通过减少核因子-kappa B(NF-kappa B p65)和促炎细胞因子的表达，上调I-kappa B-α的表达而发挥抗炎作用。替米沙坦或硝苯地平同时上调核因子红系2相关因子2(NRF2)的表达，并上调HO-1和NADPH-Q氧化还原酶1的水平。综上所述，本研究为替米沙坦和硝苯地平对铜酮诱导的小鼠脱髓鞘和行为障碍的保护作用提供了证据，可能是通过调节核因子-kappaB和Nrf2信号通路来实现的。
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-kappa B p65) as well as pro-inflammatory cytokines and elevating the expression of I kappa B-alpha. 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-kappa B and Nrf2 signaling pathways.