Synchronous Dosing of Levodopa with Quercetin Enhances Therapeutic Efficacy and Mitigates Apoptotic Events in Experimental Parkinsonism

Abstract

Parkinson’s disease (PD) affects millions of people annually across the globe and is primarily managed through dopamine replacement therapy employing levodopa (L-DOPA), which is still the preferred gold standard. Prolonged use of L-DOPA leads to severe adverse effects, including motor complications such as L-DOPA-induced dyskinesia, which considerably compromise treatment outcomes and patients’ quality of life. Potentiating L-DOPA with natural or synthetic compounds with less toxicity and neuroprotective activity is an area of emerging significance, and many studies in this area have gained widespread research attention. Phytochemicals, essentially compounds with antioxidant and neuroprotective activity, may be potent candidates to potentiate L-DOPA, and in this context, we explored the potential of combining quercetin with L-DOPA to mitigate rotenone-induced PD using human neuroblastoma cells. The optimal nontoxic concentrations of L-DOPA and quercetin were determined via the MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] assay. The combination treatment notably increased cell viability to 95% at a concentration of 6.25 μg/ml, whereas the viability of the rotenone-treated group was 46.8%. Lactate dehydrogenase leakage assays further confirmed that membrane integrity was significantly preserved in the combination-treated groups compared with those treated with L-DOPA or quercetin alone. Morphological improvements were evident under microscopic observation. Compared with the individual treatments, the combination treatment also resulted in increased inhibition of acetylcholinesterase activity. Additionally, apoptosis induction was significantly reduced in the combination group, as shown by EtBr/acridine orange fluorescence staining. Cellular calcium levels, which were elevated by rotenone exposure, were effectively normalized by the combination treatment. Moreover, the combination therapy promoted neurite outgrowth more effectively than L-DOPA or quercetin alone. These findings suggest that coadministration of quercetin with L-DOPA could be a promising strategy to increase the efficacy of L-DOPA while potentially reducing its dosage, leveraging the benefits of natural phytochemicals in PD management.