Abstract
Wilson’s disease (WD) is an autosomal recessive disease caused by mutation of the ATPase copper transporting β (ATP7B) gene, resulting in abnormal copper metabolism. We aimed to investigate the protective effect of GanDouLing (GDL) on neural stem cell (NSC) function in a mouse model of WD. NSCs were treated with different concentrations of GDL alone or in combination with penicillamine, following which we evaluated cellular growth, apoptosis, and differentiation. Nuclear factor E2-related factor 2 (Nrf2) pathway and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation were analyzed via Western blotting. Treatment with GDL alone or in combination with penicillamine significantly increased proliferation and inhibited apoptosis of NSCs in a dose-dependent manner. In addition, GDL treatment remarkably promoted differentiation of NSCs. Consistently, levels of class III β-tubulin (Tuj1) and microtubule-associated protein 2 (MAP2) were significantly elevated, whereas glial fibrillary acidic protein (GFAP) levels were obviously suppressed in the presence of GDL or penicillamine. In vivo assays confirmed that GDL increased the ratio of Ki67+, Tuj1+, and MAP2+ cells and suppressed apoptosis in the hippocampal region in WD mice. Behavioral assays revealed that both GDL and penicillamine improved memory ability in WD models. Mechanistically, GDL treatment led to activation of Nrf2 signaling and suppression of the NLRP3 inflammasome in WD mice. Notably, inhibition of Nrf2 signaling reversed the protective effects of GDL on hippocampal NSCs. Collectively, these findings demonstrate that GDL exerts a protective effect on NSCs and promotes neurogenesis by targeting Nrf2 signaling and the NLRP3 inflammasome in WD.
Highlights
Wilson’s disease (WD) is a rare autosomal recessive disorder of copper metabolism that manifests as copper poisoning in various tissues and organs, especially the liver, brain, cornea, and kidneys [1]
transferase d-UTP nick-end labeling (TUNEL) assays were performed to evaluate the effect of GDL treatment on apoptosis of neural stem cell (NSC)
Relative to those observed in the control group, rates of apoptosis were obviously decreased in NSCs treated with GDL or penicillamine alone or in combination (Figure 1E,F)
Summary
Wilson’s disease (WD) is a rare autosomal recessive disorder of copper metabolism that manifests as copper poisoning in various tissues and organs, especially the liver, brain, cornea, and kidneys [1]. The global prevalence of WD is between 1 in 5000 and 1 in 30000. The genetics of WD is complex, with more than 450 disease-causing mutations identified. Trans-membrane ATPase copper transporting β (ATP7B) in hepatocytes plays a predominant role in the pathogenesis of WD. An absence of functional ATP7B protein results in decreased hepatocellular excretion of copper into bile. Clinical manifestations of WD vary from an asymptomatic state to acute hepatic failure, chronic liver disease, and neurological symptoms. The need to develop novel therapeutic drugs and identify the mechanisms underlying their efficacy in WD remains urgent
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