Neuroprotective Effects of Lycopene in Parkinson's Disease Mice: Potential Modulation of DAT/SLC6A3-Mediated Dopaminergic Pathway.

Background/Objectives: Lycopene (LYC), a natural lipid-soluble antioxidant extracted from dietary plants, possesses excellent neuroprotective and metabolic regulatory activities and has shown potential preventive and therapeutic effects on neurodegenerative diseases. However, its precise molecular mechanism against Parkinson's disease (PD) remains incompletely clarified, which limits its further application. Methods: In this study, a PD mouse model was established, and a series of methods, including molecular docking, untargeted metabolomics, behavioral tests, and histopathological analysis, were used. Results: The results showed that LYC intervention not only improved the motor coordination ability of mice and reduced dopaminergic neuron damage but also reversed the metabolic disorders caused by the disease. Importantly, LYC can significantly increase the expression level of DAT/SLC6A3 in the midbrain region, and this is evident at both the gene and protein levels. Computational simulations and surface plasmon resonance results show that LYC can form stable complexes with the DAT/SLC6A3 protein and has a high affinity. Conclusions: This study explored the potential anti-PD effects of LYC from multiple perspectives and observed an association between elevated DAT/SLC6A3 levels and improved dopamine (DA) homeostasis after LYC intervention. These preliminary findings may offer new experimental clues for further mechanistic study and translational research on PD prevention and treatment.