Ellagic acid’s dual targeting of Dmt1 uptake and Nrf2 defense counters juvenile manganese neurotoxicity

Manganese (Mn) is an environmental neurotoxicant that threatens paediatric health through contaminated water. We evaluated the potential of ellagic acid (EA), a dietary polyphenol in nuts/berries, against multi-organ Mn toxicity. Juvenile male rats (n = 35) were divided into: control (distilled water), Mn (100 mg/kg MnCl₂), EA (30 mg/kg), vehicle, and Mn+EA groups. After 28 days of oral treatment, behavioral tests (OFT, EPM, ART) were conducted. Tissues were analyzed for oxidative stress (SOD, CAT, MDA), neuroinflammation (TNF-α), dopamine, AChE, gene expression (DMT1, Nrf2, Sod1), and histopathology. Mn induced locomotor deficits, anxiety-like behaviour, sensorimotor hyper-reactivity, oxidative stress (↓SOD/CAT, ↑MDA), elevated TNF-α, and reduced dopamine. EA co-treatment reversed behavioural impairments, restored antioxidant activity, normalized TNF-α/dopamine, EA suppressed Mn-induced Dmt1 upregulation, a key compensatory Mn uptake pathway in juveniles, while activating Nrf2, representing a novel dual protective mechanism. Histology confirmed EA preserved neuronal integrity and reduced hepatorenal damage. In conclusion, EA-associated downregulation of Dmt1 and downstream biochemical/histological improvements provide indirect evidence consistent with reduced Mn influx, but requires confirmation by direct brain Mn quantification.