Plant-derived soft electrophiles upregulate pro-resolving oxylipins in a paraquat-induced Drosophila model of Parkinson's disease.

Age-accompanied chronic, low-grade systemic inflammation (inflammaging) drives the onset and progression of neurodegenerative disorders like Parkinson's disease (PD). Currently, no disease-modifying therapies are available for PD. Exposure to environmental toxicants, including paraquat (PQ), rotenone, and neurotoxic metals, increases disease risk. Conversely, sustained consumption of dietary soft electrophiles, such as flavonoids, carotenoids, vitamin E vitamers, and essential fatty acids, has been associated with increased lifespan and delayed age-related neurological decline. Omega-3 and select omega-6 fatty acids also serve as precursors of lipid-derived specialized pro-resolving mediators (SPMs), which exert potent anti-inflammatory and inflammation-resolving activities. Here, we report the development of a robust analytical method to quantify pro-resolving oxylipins in a PQ-induced Drosophila melanogaster model of PD, enabling investigation of how dietary phytochemicals modulate anti-inflammatory and pro-resolving lipid metabolism in vivo. We hypothesized that plant-derived soft electrophiles promote active resolution of neuroinflammation by enhancing the production of pro-resolving oxylipins derived from essential fatty acids, and that their neuroprotective effects are linked to their soft electrophilic properties. Our results demonstrate that specific lipophilic plant-derived soft electrophiles significantly upregulate pro-resolving oxylipins in Drosophila heads following PQ exposure. We identify a subset of flavones and structurally related phytochemicals that selectively enhance SPM biosynthesis and show that this response involves the NF-κB orthologue relish. Additionally, feeding modality and sex-specific dimorphisms were found to influence oxylipin production. Collectively, these findings indicate that structurally related dietary soft electrophiles enhance endogenous pro-resolving lipid pathways, promote resolution of toxin-induced neuroinflammation, and have potential preventive and therapeutic relevance for neuroinflammation-associated neurodegenerative diseases.