Computational Discovery and <i>In Vivo</i> Validation of Fenchone as a Neuroprotective Agent Targeting the D2 Dopamine Receptor in Parkinson’s Disease

In this study, we assessed the neuroprotective efficacy of the bicyclic monoterpene fenchone in a rotenone-induced rat model of Parkinson’s disease through integrated in silico and in vivo investigations. Molecular modeling indicated that fenchone is very lipophilic (Log [Formula: see text]) and contains a mostly hydrophobic pharmacophore. It showed good binding affinity with the dopamine [Formula: see text] receptor (–5.84 kcal/mol) and similar results to those obtained from levodopa (–5.7 kcal/mol). The results of density functional theory revealed that fenchone has high chemical hardness (3.175 eV) and a large HOMO–LUMO energy gap (6.35 eV), indicating molecular stability. The stability of the fenchone–dopamine [Formula: see text] receptor complex in molecular dynamics for 100 ns was confirmed by stable root mean square deviation values and radius of gyration. In vivo, fenchone (200 mg/kg) treatment significantly improved motor performance by decreasing pole test latency and restoring stair test, wood walk test, wire hang and rotarod performance. Biochemical analyses demonstrated that fenchone normalized dopamine levels, increased the activities of antioxidant markers such as catalase and superoxide dismutase and reduced glutathione levels while decreasing malondialdehyde levels. Histopathologically, nigral neurons were preserved in the presence of levodopa. Taken together, our results suggest that fenchone has the potential to be a novel multimodal disease-modifying agent for PD by acting on the dopamine [Formula: see text] receptor and exerting antioxidant and neuroprotective effects.