Deferiprone mitigates imidacloprid-induced neurotoxicity: Roles of iron chelation, ferroptosis, and ferritinophagy.

Imidacloprid (IMI) is a commonly used chloronicotinyl insecticide, although it has low specificity to humans, long-term exposure would induce neurotoxicity through cholinergic signaling disruption and ferroptosis activation. The current investigation aimed to explore the neuroprotective impact of deferiprone (DFP), an iron chelator, against IMI-induced neurotoxicity and whether co-administration with everolimus (EVR), an mTOR inhibitor known to induce autophagy and potentially enhance ferritinophagy, would alter this effect. Adult male Wistar rats were assigned randomly to four different experimental sets: control, IMI, IMI + DFP, and IMI + DFP + EVR groups. They were given IMI (90 mg/kg/day, p.o.), DFP (125 mg/kg/day, p.o.), and EVR (1 mg/kg/day, i.p.) for 30 days. Rats were subjected to neurobehavioral assessments including open-field, rotarod, Y-maze, and tail-immersion tests. Rats' cortices were examined histologically, and acetylcholinesterase (AChE) expression was evaluated immunohistochemically. Several biochemical markers were assessed including oxidative stress markers such as reduced and oxidized glutathione, superoxide dismutase and malondialdehyde, in addition to ferroptotic markers including acyl-CoA synthetase long-chain family member-4, lysophosphatidylcholine acyltransferase-3, iron responsive element binding protein-2, ferritin heavy chain-1, and transferrin receptor-1. IMI administration led to marked biochemical derangements, cortical damage, reduced AChE expression, altered spontaneous motor function, locomotor coordination, spatial memory, and pain threshold while increasing anxious behaviours. DFP ameliorated oxidative stress, reduced ferroptotic markers and alleviated the neurobehavioural defects. Meanwhile, co-administration of EVR abolished these protective effects, consistent with enhanced autophagy-associated iron release and ferroptosis activation. Overall, these findings support the therapeutic potential of DFP against IMI-induced neurotoxicity and highlight ferroptosis as a promising therapeutic target in pesticide-related neurodegeneration.