The protective effect of inosine against rotenone-induced Parkinson's disease in mice; role of oxido-nitrosative stress, ERK phosphorylation, and A2AR expression.

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-α, 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 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.