The protective effect of inosine against rotenone-induced Parkinson's disease in mice; role of oxido-nitrosative stress, ERK phosphorylation, and A2AR expression
The protective effect of inosine against rotenone-induced Parkinson's disease in mice; role of oxido-nitrosative stress, ERK phosphorylation, and A2AR expression
复制标题
DOI：
10.1007/s00210-019-01804-1
复制
发表时间：
2020-06-01
影响因子：
3.6
通讯作者：
Messiha, Basim A. S.
中科院分区：
文献类型：
--
作者：
EI-Shamarka, Marwa E. A.;Kozman, Magy R.;Messiha, Basim A. S.
帕金森病（PD）是一种严重的致残性综合征，其中神经炎症和各种信号通路被认为介导多巴胺能神经变性。在这里，嘌呤核苷肌苷可能的疾病修饰作用对鱼藤酮诱导的PD进行了检查。将小鼠分为六组，即接受二甲亚砜的正常对照组、接受鱼藤酮的PD对照组、接受左旋多巴/卡比多巴与鱼藤酮的标准治疗组以及接受低、中、高剂量肌苷与鱼藤酮的三个治疗组。实验结束时，进行三项行为测试以评估PD运动表现，即挂线测试、走木测试和楼梯测试。行为学研究结束后，分离小鼠纹状体进行次黄嘌呤比色测定，多巴胺、肿瘤坏死因子-α、白细胞介素-6和亚硝酸盐的酶联免疫吸附测定，总细胞外信号调节激酶和磷酸化细胞外信号调节激酶的Western blot测定（tERK和pERK），腺苷A（2A）受体（A2 AR）表达的聚合酶链反应估计，以及黑质和纹状体组织的组织病理学检查。肌苷以剂量依赖性方式防止PD进展，其效果与标准治疗L-多巴/卡比多巴相当，通过行为，生化和组织学结果证明。肌苷的有益抗帕金森病作用可归因于药物改善神经炎症和氧化亚硝化应激的能力，以及ERK磷酸化的抑制和A2 AR表达的下调。因此，肌苷可以被认为是一种针对PD的疾病改善剂，但进一步的研究声称可以在临床上证实这种作用。
Parkinson's disease (PD) is a severe disabling syndrome in which neuroinflammation and various signaling pathways are believed to mediate dopaminergic neurodegeneration. Here, the possible disease-modifying effects of the purine nucleoside inosine were examined against rotenone-induced PD. Mice were allocated into six groups, namely, a normal control group receiving dimethylsulfoxide, a PD control group receiving rotenone, a standard treatment group receiving L-dopa/carbidopa together with rotenone, and three treatment groups receiving inosine in low, medium, and high doses together with rotenone. At the end of the experimental protocol, three behavioral tests were performed to assess PD motor manifestations, namely, wire-hanging test, wood-walking test, and stair test. After performing the behavioral study, mice striata were isolated for the colorimetric assay of hypoxanthine, the enzyme-linked immunosorbent assay of dopamine, tumor necrosis factor-alpha, interleukin-6 and nitrite, the Western blot estimation of total and phosphorylated extracellular signal-regulated kinase (tERK and pERK), the polymerase chain reaction estimation of adenosine A(2A) receptor (A2AR) expression, as well as the histopathological examination of substantia nigra and striatal tissue. Inosine protected against PD progression in a dose-dependent manner, with the effect comparable to the standard treatment L-dopa/carbidopa, evidenced by behavioral, biochemical, and histologic findings. The beneficial antiparkinsonian effect of inosine could be attributed to the ability of the drug to ameliorate neuroinflammation and oxido-nitrosative stress, together with suppression of ERK phosphorylation and down-regulation of A2AR expression. Inosine could therefore be considered as a disease-modifying agent against PD, but further studies are claimed to confirm such effects clinically.