Abstract
Objective Gandouling (GDL) tablet is a Chinese patent medicine approved by the National Medical Product Administration, which is used to treat Wilson disease (WD) in China. In this study, we aimed to investigate the effects of GDL on mitophagy in the hippocampus in the toxic milk (TX) mouse model of WD. Methods Mice were randomly divided into the following four groups: control, Wilson (model group), D-penicillamine (DPA), and GDL groups. The animal behaviors were evaluated by the water maze experiment, traction test, and pole test. Transmission electron microscopy was used for the detection of mitochondrion structure. An enzyme-linked immunosorbent assay (ELISA) was performed for the analysis of the changes in liver function. Colocalization of mitophagy-related proteins was detected by fluorescence microscopy. Western blotting (WB) and reverse transcription-polymerase chain reaction (RT-PCR) were conducted for the detection of protein expression and mRNA levels, respectively. Results Significant reduction in neurological impairments was observed in the WD model group. All of these results were significantly reversed by GDL intervention. Compared with the levels in the Wilson group, the levels of alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), and albumin (ALB) changed obviously. Colocalization between mitophagy-related proteins pink1, parkin, and mitochondria was changed significantly. The mitophagy-related mRNA (pink1, parkin, and LC3II) and protein expression levels (pink1, parkin, and the rate of LC3II/LC3I) were decreased significantly, while p62 was remarkably increased after GDL intervention. Conclusion Our findings indicated that the neuroprotective mechanism of GDL may occur via the inhibition of excessive mitophagy through the regulation of the pink1/parkin pathway in the TX mouse brain of WD.
Highlights
Wilson’s disease (WD) is an inborn error of copper metabolism, which is caused by autonomic recessive inheritance.is rare disease is caused by mutations in the gene encoding a copper-transporting P-type ATPase (ATP7B), which is critical for copper excretion in the bile, resulting in copper accumulation, mainly in the liver, brain, cornea, and kidney [1]
We aimed to explore the effects of GDL treatment on mitophagy and mitochondrial function through the Pink1/parkin pathway in the toxic milk (TX) mouse model of WD
We found that mitophagy was involved in neurological injury in WD mice and that GDL may inhibit the mitophagy in the hippocampus via regulation of the pink/parkin pathway
Summary
Wilson’s disease (WD) is an inborn error of copper metabolism, which is caused by autonomic recessive inheritance. Is rare disease is caused by mutations in the gene encoding a copper-transporting P-type ATPase (ATP7B), which is critical for copper excretion in the bile, resulting in copper accumulation, mainly in the liver, brain, cornea, and kidney [1]. WD is lethal if left untreated, but it has been reported to be one of the rare inherited diseases for which effective pharmacologic treatment can be applied. Excessive inorganic copper induces oxidative stress and leads to multisystem and multiorgan dysfunction [5,6,7]. A recent study has shown that apoptosis, autophagy, and mitochondrial dysfunction are involved in excessive copper induced-oxidative stress damage in male germ cells [8]
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