Background and aims <p>Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons, leading to motor and non-motor symptoms. Oxidative stress and inflammation are key contributors to PD pathogenesis, yet current treatments primarily focus on dopamine replacement and fail to address these underlying mechanisms. This study investigates the neuroprotective potential of a combination of five compounds—N-acetylcysteine (NAC), resveratrol, quercetin, selenium, and coenzyme Q10 (CoQ10)—in a zebrafish model of PD induced by rotenone.</p> Methods <p>Eighty adult male zebrafishes were divided into eight groups, including control, rotenone-only, and groups treated with individual compounds or the combination (2QRNS). Motor activity, dopamine levels, and expression of genes related to oxidative stress, apoptosis, autophagy, and inflammation were assessed.</p> Results <p>Results showed that rotenone significantly reduced motor activity and dopamine levels, while the 2QRNS cocktail, selenium, and resveratrol were most effective in mitigating these effects. Selenium notably enhanced the expression of antioxidant genes (superoxide dismutase and glutathione peroxidase) and inhibited apoptosis and autophagy pathways. Resveratrol demonstrated strong anti-inflammatory effects by reducing interleukin-6 (IL-6) expression.</p> Conclusion <p>These findings suggest that the 2QRNS combination, particularly selenium and resveratrol, offers significant neuroprotection in a PD model by targeting oxidative stress, inflammation, and cell death pathways. Further studies on other PD models and detailed molecular pathways are recommended to validate these results and explore their clinical potential.</p>