Abstract

Parkinson’s disease (PD) is characterized by progressive neurodegeneration, oxidative stress, and neurotransmitter imbalance. This study investigated the neuroprotective potential of D-ribose-L-cysteine (RibCys) and lauric acid (LA), alone and in combination, in an α-synuclein transgenic Drosophila melanogaster model of PD. Flies were divided into five groups: control, untreated PD, PD + RibCys, PD + LA, and PD + RibCys + LA, and were fed supplemented diets for 21 days. Behavioral, biochemical, and molecular parameters were evaluated. Treatment with RibCys and/or LA significantly ( p  < 0.05) prolonged lifespan and improved locomotor and olfactory functions compared to untreated PD flies. The combination therapy produced superior outcomes relative to monotherapies. Antioxidant parameters (total thiols, SOD, CAT) were restored, while oxidative markers (MDA, H₂O₂, NO) were markedly reduced ( p  < 0.05) in treated groups, with the combination therapy showing the most significant effects ( p  < 0.05). Neurochemical profiling revealed restoration of dopamine and serotonin levels and normalization of acetylcholine concentrations. Furthermore, treatment downregulated pro-inflammatory (TNF-α) and apoptotic (caspase-3) markers and inhibited MAO and AChE activities. Upregulation of Ddc and DAT gene expression was also observed in treated PD flies. These findings demonstrate that RibCys and LA confer neuroprotection through antioxidant, anti-inflammatory, anti-apoptotic, and neurotransmitter-modulatory mechanisms. The combinatorial therapy exhibited the greatest efficacy, supporting its potential as a candidate nutraceutical intervention. This work contributes to the growing field of nutritherapeutics and provides mechanistic insight for the development of adjunctive strategies for PD management. Graphical abstract