Melatonin ameliorates copper accumulation-induced cognitive impairment in Wilson disease via activation of the SIRT3/FOXO3α signaling pathway.

Wilson disease (WD) was identified as a copper (Cu)-overload disorder characterized by disrupted Cu metabolism that caused multi-system damage. Accumulating clinical evidence indicated that cognitive deficits were present in patients with WD, yet the underlying mechanism remained unclear. In this work, clinical observations were first performed on 18 patients with WD associated mild cognitive impairment (WD-MCI). The pineal gland volume was found to be significantly reduced, and serum melatonin levels were markedly decreased. A correlation was observed between the abnormal melatonin secretion resulting from pineal gland atrophy and the decline in cognitive ability. This study further conducted animal experiments to explore its mechanism. Mice were allocated into a normal control group (NC group), the Wilson disease model TX mouse group (WD group), the dimercaptosuccinic acid-treated TX mouse group (DMSA group), and the melatonin-treated TX mouse group (MEL group). Cognitive function, hippocampal histomorphology, and the expression of proteins related to hippocampal oxidative stress, inflammation, autophagy, and apoptosis were assessed. Oxidative stress was evaluated by measuring the levels of malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), catalase (CAT), and reactive oxygen species (ROS) in hippocampal tissues. Serum levels of melatonin, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were detected. Mitochondrial damage was examined via ultrastructural analysis and mitochondrial membrane potential (MMP) monitoring. The results demonstrated that the beneficial effects of melatonin were mediated through the activation of the SIRT3/FOXO3a pathway, suppression of inflammatory factors, and reduction in mitophagy, thereby inhibiting hippocampal neuronal apoptosis and improving cognitive function.