DEFERIPRONE AND FERULIC ACIDS AMELIORATE ALCOHOL-INDUCED COGNITIVE IMPAIRMENT BY MODULATING IRON METABOLISM AND INHIBITING FERROPTOSIS IN THE STRIATUM

While alcohol-induced cognitive impairment and iron overload are recognized, the precise mechanisms linking alcohol to altered brain iron metabolism and subsequent cognitive decline remain unclear. This study investigated alcohol's impact on iron metabolism genes in cognitive brain regions and evaluated Deferiprone (DFP) and ferulic acids (FA) as iron chelators for alcohol-induced memory impairment by modulating iron metabolism and ferroptosis. Mice received alcohol (2.5 or 5 g/kg) orally for 28 days, then underwent behavioral testing. Alcohol-treated mice exhibited dose-dependent cognitive impairment in Y-maze and novel object recognition tests. Alcohol administration significantly increased ferrous iron levels in the hippocampus, striatum and serum, negatively correlating with cognitive scores. Striatal expression of iron metabolism genes (transferrin-receptor-1 (TFR1), divalent-metal-transporter-1 (DMT1), iron-regulatory-protein-2 (IRP2)) also increased. Concurrent DFP (20 mg/kg) or FA (40 mg/kg) significantly reversed alcohol-induced cognitive deficits in Y-maze and Barnes maze. Both compounds significantly ameliorated the increased protein expressions of TFR1 and IRP2, with FA also reducing DMT1. DFP and FA effectively suppressed alcohol-induced ferroptosis markers in the striatum, including elevated malondialdehyde and acyl-CoA-synthetase-long-chain-family-member-4 (ACSL4), and decreased Glutathione-Peroxidase-4 (GPX4). Furthermore, DFP and FA treatment counteracted reduced neuronal area, restored protein expressions of synaptophysin (SYP) and postsynaptic-density-protein-95 (PSD95), and notably ameliorated mitochondrial ultrastructural damage in the striatum, characterized by reduced matrix vacuolization and partial restoration of cristae structure. In conclusion, DFP and FA attenuated alcohol-induced cognitive impairment in mice by normalizing iron metabolism, suppressing oxidative stress, protecting synapses and mitochondrial morphology, enhancing neuronal survival, and inhibiting ferroptosis in the striatum.