Network pharmacology-based approach to understand the effect and mechanism of chrysophanol against cognitive impairment in Wilson disease.

Wilson disease (WD) is a rare hereditary copper metabolism disorder, wherein cognitive impairment is a common clinical symptom. Chrysophanol (CHR) is an active compound with neuroprotective effects. The study aims to investigate the neuroprotective effect of CHR in WD and attempted to understand the potential mechanisms. Network pharmacology analysis was applied to predict the core target genes of CHR against cognitive impairment in WD. The rats fed with copper-laden diet for 12 weeks, and the effect of CHR on the copper content in liver and 24-h urine, the learning and memory ability, the morphological changes and the apoptosis level of neurons in hippocampal CA1 region, the expression level of Bax, Bcl-2, Cleaved Caspase-3, p-PI3K, PI3K, p-AKT, and AKT proteins were detected. Network pharmacology analysis showed that cell apoptosis and PI3K-AKT signaling pathway might be the main participants in CHR against cognitive impairment in WD. The experiments showed that CHR could reduce the copper content in liver, increase the copper content in 24-h urine, improve the ability of the learning and memory, alleviate the damage and apoptosis level of hippocampal neurons, down-regulate the expression of Bax, Cleaved Caspase-3, and up-regulate the expressions of Bcl-2, p-PI3K/PI3K, p-AKT/AKT. These results suggested that CHR could alleviate cognitive impairment in WD by inhibiting cell apoptosis and triggering the PI3K-AKT signaling pathway.