Luteolin attenuates trimethyltin chloride-induced hippocampal neurotoxicity through SIRT3/NRF2/HO-1 activation

Trimethyltin chloride (TMT), a potent neurotoxicant, induces hippocampal damage associated with neuroinflammation and synaptic dysfunction, mimicking key features of neurodegenerative disorders. Luteolin (LUT), a natural flavonoid with anti-inflammatory and neuroprotective properties, has emerged as a promising therapeutic candidate. This study investigated the neuroprotective effects of LUT against TMT-induced hippocampal damage and explored the underlying mechanisms involving the SIRT3/NRF2/HO-1 signaling pathway. In a murine model, LUT treatment (20 mg/kg, 14 days) significantly alleviated TMT-induced behavioral deficits, seizures, and ultrastructural hippocampal damage. Mechanistically, LUT restored synaptic protein expression (PSD95, SYN1, SYP) and suppressed neuroinflammation by reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-18) and glial activation (GFAP, IBA1). In vitro studies using SIRT3 inhibition confirmed the pathway's centrality to LUT's effects. These results position LUT as a multi-target therapeutic candidate for hippocampal-related disorders, with dual efficacy in synaptic repair and anti-inflammatory modulation. Critically, this work bridges preclinical findings to clinical translation, suggesting LUT's applicability in neurotoxicant exposure scenarios or early neurodegenerative disease interventions. Further validation of bioavailability and safety profiles could accelerate its transition to clinical trials.