Gandouling alleviates cognitive dysfunction by regulates the p62/Nrf2 signaling pathway to reduce oxidative stress and autophagy in mice models of Wilson’s disease

Cognitive impairment is a neurological manifestation of Wilson's disease (WD). Gandouling (GDL), a traditional Chinese medicine, protects against WD-related brain damage. However, the mechanisms underlying its protective effect have not been elucidated. Therefore, we explored the neuroprotective effects of GDL on cognitive abilities to understand the underlying molecular mechanisms using a toxic milk mouse model of WD. We employed the Morris water maze test and open field test to assess the effects of GDL on spatial memory, learning abilities and exploratory behavior in these mice. GDL treatment reduced the escape latency and increased the number of times mice crossed the platform to reach the target zone, indicative of alleviated WD-associated cognitive dysfunction. It also ameliorated the histopathological changes in the hippocampus via downregulation of IL-1β, IL-6, and TNF-α expression, reduced oxidative stress, and increased cell vigor. GDL treatment increased the protein and mRNA levels of Nrf2 and OH-1 protein while lowering p62, Beclin1, and LC3 expression in the hippocampus. Collectively, GDL improves cognitive dysfunction in mice with WD by regulating the Nrf2/p62 signaling pathway by reducing oxidative stress and autophagy. Based on its anti-inflammatory, antioxidant, and autophagy-inhibiting effects, we believe GDL is a promising therapy for WD-related cognitive dysfunction.