Quercetin parallels ascorbic acid in neuroprotection against manganese-induced toxicity in Drosophila melanogaster

Quercetin (QCT) is a dietary flavonoid with reported antioxidant and neuroprotective properties, but direct comparisons with established antioxidants, such as ascorbic acid (AA), under chemically induced neurotoxic stress are limited. We compared Quercetin and AA in adult D. melanogaster using a manganese (Mn)-sensitized model to capture Parkinson-like motor and biochemical vulnerability. Treatment groups comprised: Control; Mn (15 mM); AA (10 mM); Quercetin 0.5 mM/3.0 mM; AA + Mn; Quercetin 0.5 mM/3.0 mM + Mn. Each vial represented an independent biological replicate (mixed sex); biochemical and genomic assays were performed using n = 4 vials/group. Outcomes included survival, locomotor performance (RING), redox endpoints (GSH/GSSG, H₂O₂, MDA, SOD, CAT), neuromodulators (AChE, dopamine), DNA fragmentation index (DFI), and advanced glycation end-products (AGEs). Omnibus tests (ANOVA or Kruskal-Wallis) were followed by Tukey HSD or Dunn-style pairwise comparisons; two pre-specified pooled contrasts were tested with Welch comparisons and effect sizes reported (mean differences, 95% CI, Cohen’s d); pooled p-values were adjusted (Holm, BH). Quercetin and AA produced comparable protective effects, as both preserved climbing behaviour and partially restored the redox balance versus Mn. One Tukey-adjusted pairwise result reached significance (Control vs. quercetin low + Mn for DFI, p_adj = 0.049). A pooled contrast showed reduced H₂O₂ for Quercetin (Q_all vs. AA_all: mean diff = 0.498 µmol·g⁻¹, 95% CI 0.153–0.844; Welch t(13.27) = 3.11, p = 0.0082; d ≈ 1.38), but this and other pooled signals did not survive conservative family-wise correction across all pooled tests. In conclusion, although they are overall comparable, our data suggest that quercetin may have a superior, specific effect on reducing H₂O₂ and protecting DNA integrity (DFI). These endpoints are now prioritized for confirmatory studies. Quercetin and ascorbic acid (vitamin C) produced comparable neuroprotective effects in manganese-sensitized D. melanogaster, preserving locomotor performance and attenuating oxidative stress. A pooled contrast indicated a considerable reduction in H₂O₂ and DFI with Quercetin compared to AA, suggesting that H₂O₂ and DFI might be prioritized endpoints. Several endpoints (GSSG/GSH balance, AGEs) showed large effect sizes favouring quercetin in pooled contrasts. However, these signals did not survive conservative family-wise correction across the whole test family; therefore, the results are hypothesis-generating.