Trigonelline, a Natural Alkaloid, Mitigates Nanoplastic-Induced Neurotoxicity by Restoring Mitochondrial Function and Redox Homeostasis in Drosophila Melanogaster

Nanoplastics (NPs) are emerging environmental contaminants that readily enter the food chain and can accumulate in the brain, contributing to neurotoxicity. Despite growing evidence of these adverse effects, effective natural interventions to mitigate NPs-induced neurotoxicity remain largely unexplored. Therefore, this study evaluated the neuroprotective efficacy of trigonelline (TG), a natural alkaloid, against polystyrene nanoplastic (PS-NPs)-induced neurotoxicity in a Drosophila melanogaster model using an integrated assessment of behavioral, neurochemical, mitochondrial, biochemical, molecular, and computational endpoints. TG supplementation significantly improved locomotor performance, circadian rhythmicity, and survival while preserving dopaminergic neurons, restoring tyrosine hydroxylase (TH) activity and dopamine levels, and modulating HVA levels. TG also restored mitochondrial membrane potential, respiratory chain complex I and IV activities, ATP production, antioxidant enzyme activities, and PI3K/Akt/TOR-associated gene expression, while reducing intracellular and mitochondrial reactive oxygen species, lipid peroxidation, lipid droplet accumulation, and apoptosis-associated gene expression. Complementary network pharmacology and molecular docking analyses identified oxidative stress-related pathways and predicted a potential interaction between TG and tyrosine hydroxylase. These findings suggested that trigonelline confers neuroprotection against NPs-induced toxicity by improving behavioral function, preserving dopaminergic integrity, restoring mitochondrial homeostasis, and attenuating oxidative stress, thereby supporting its potential as a promising natural neuroprotective candidate for mitigating NPs-associated neuronal damage.