Abstract
OBJECTIVE: Melatonin has been shown to have neuroprotective effects. This study is aimed at observing the effects of copper deposition on cognitive function in a toxic milk (TX) mouse model of Wilson disease (WD), and investigating the effects and mechanisms of action of Gandou Bushen Decoction (GDBSD) on melatonin synthesis and pineal function in the WD model mice. METHODS: A total of 30 homozygous TX mice were randomly assigned to 3 groups (n = 10 in each group), including a WD group, a GDBSD group, and a dimercaptosuccinic acid (DMSA) group. A total of 10 DL mice were included in the normal control (NC) group. The structure and copper content of pineal gland tissues, oxidative stress and apoptosis-related markers, and serum melatonin levels were evaluated using hematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and Western blot. RESULTS: Compared with the NC group, the WD group exhibited decreased learning and cognitive abilities (P < 0.05), damaged pineal gland structure, increased copper content, reactive oxygen species (ROS) levels, and mitochondrial damage rate in the pineal gland (P < 0.01), altered levels of melatonin and oxidative stress-related markers (P < 0.05), upregulated expression levels of pro-apoptotic proteins Bax and Caspase-3, and decreased expression of the anti-apoptotic protein Bcl-2 (P < 0.01). After treatment with GDBSD and DMSA, the SIRT3/FOXO3α signaling pathway was activated, the copper content in the pineal gland was reduced, and oxidative stress and apoptosis-related damages were improved, leading to an improvement in learning and memory abilities (P < 0.05). CONCLUSION: GDBSD can alleviate cognitive impairments in WD mice caused by pineal gland copper deposition by inhibiting oxidative stress and apoptosis in the pineal gland. The underlying molecular mechanism is associated with the regulation of the SIRT3/FOXO3α signaling pathway.