Inosine attenuates rotenone‐induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis

Abstract

Growing evidence points to impaired autophagy as one of the major factors implicated in the pathophysiology of Parkinson's disease (PD). Autophagy is a downstream target of adenosine monophosphate‐activated protein kinase (AMPK). Inosine has already demonstrated a neuroprotective effect against neuronal loss in neurodegenerative diseases, mainly due its anti‐inflammatory and antioxidant properties. We, herein, aimed at investigating the neuroprotective effects of inosine against rotenone‐induced PD in rats and to focus on the activation of AMPK‐mediated autophagy. Inosine successfully increased p‐AMPK/AMPK ratio in PD rats and improved their motor performance and muscular co‐ordination (assessed by rotarod, open field, and grip strength tests, as well as by manual gait analysis). Furthermore, inosine was able to mitigate the rotenone‐induced histopathological alterations and to restore the tyrosine hydroxylase immunoreactivity in PD rats' substantia nigra. Inosine‐induced AMPK activation resulted in an autophagy enhancement, as demonstrated by the increased striatal Unc‐S1‐like kinase1 and beclin‐1 expression, and also by the increment light chain 3II to light chain 3I ratio, along with the decline in striatal mammalian target of rapamycin and p62 protein expressions. The inosine‐induced stimulation of AMPK also attenuated neuronal apoptosis and promoted antioxidant activity. Unsurprisingly, these neuroprotective effects were antagonized by a preadministration of dorsomorphin (an AMPK inhibitor). In conclusion, inosine exerted neuroprotective effects against the rotenone‐induced neuronal loss via an AMPK activation and through the restoration of the imbalance between autophagy and apoptosis. These findings support potential application of inosine in PD treatment.

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

“…Chronic rotenone exposure in rats elicits neuropathological and behavioral features mimicking the gradual progression of PD observed in humans (Xiong et al 2012 ; Johnson and Bobrovskaya 2015 ). In line, repeated exposure of rats to rotenone in the current study resulted in dopaminergic neuronal death and reduced locomotor activity, loss of grip strength, and a decrease in the fall time in the rotarod test, indicating motor impairments accompanied with severe loss of dopaminergic neurons in the SN, which are in line with previous studies (Abdelkader et al 2020 ; El-Saiy et al 2022 ; El-Latif et al 2023 ).…”