Edaravone-caffeine combination for the effective management of rotenone induced Parkinson's disease in rats: An evidence based affirmative from a comparative analysis of behavior and biomarker expression.

Restoration of cellular microenvironment is important in the treatment of neurodegenerative diseases for optimal functioning and survival of neurons. Oxidative stress has been proposed as one of the major pathogenic drivers in Parkinson's disease. Parkinson's model was developed by chronic administration of a pesticide rotenone that inhibits mitochondrial complex I resulting in generation of reactive oxygen species. In this study, our aim was to evaluate neuroprotective effect rendered by edaravone, a potent free radical scavenger in combination with caffeine, an effective inhibitor of adenosine A2A receptor as well as a proven antioxidant. Here we demonstrate that a three-week treatment with edaravone-caffeine combination was able to significantly diminish rotenone induced oxidative damage at the cellular level as well as muscle weakness and cognitive impairment generally associated with Parkinson's disease. This effect is attributable to edaravone's capability of scavenging the perxoynitrite free radical. Herein, we have assessed the levels of protein nitroxidation marker 3-nitrotyrosine in the striatum and lipid peroxidation marker malondialdehyde in striatum, cerebrospinal fluid, plasma and urine of rats. On the 21^st day, statistical difference was observed in the striatal biomarker levels (p = 0.001) between the controls, treated and untreated groups. We discovered that when edaravone was co-administered with caffeine, the effect was more significant compared to the group solely treated with edaravone demonstrating a synergistic effect. Simultaneous therapeutic intervention with drug combination showed a pronounced decrease in oxidative damage markers as well as better muscle strength and cognition compared to the untreated groups.