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Abstract
Excessive manganese (Mn) can accumulate in the striatum of the brain following overexposure. Oxidative stress is a well-recognized mechanism in Mn-induced neurotoxicity. It has been proven that glutathione (GSH) depletion is a key factor in oxidative damage during Mn exposure. However, no study has focused on the dysfunction of GSH synthesis-induced oxidative stress in the brain during Mn exposure. The objective of the present study was to explore the mechanism of Mn disruption of GSH synthesis via EAAC1 and xCT in vitro and in vivo. Primary neurons and astrocytes were cultured and treated with different doses of Mn to observe the state of cells and levels of GSH and reactive oxygen species (ROS) and measure mRNA and protein expression of EAAC1 and xCT. Mice were randomly divided into seven groups, which received saline, 12.5, 25, and 50 mg/kg MnCl2, 500 mg/kg AAH (EAAC1 inhibitor) + 50 mg/kg MnCl2, 75 mg/kg SSZ (xCT inhibitor) + 50 mg/kg MnCl2, and 100 mg/kg NAC (GSH rescuer) + 50 mg/kg MnCl2 once daily for two weeks. Then, levels of EAAC1, xCT, ROS, GSH, malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and morphological and ultrastructural features in the striatum of mice were measured. Mn reduced protein levels, mRNA expression, and immunofluorescence intensity of EAAC1 and xCT. Mn also decreased the level of GSH, sulfhydryl, and increased ROS, MDA, 8-OHdG, and carbonyl in a dose-dependent manner. Injury-related pathological and ultrastructure changes in the striatum of mice were significantly present. In conclusion, excessive exposure to Mn disrupts GSH synthesis through inhibition of EAAC1 and xCT to trigger oxidative damage in the striatum.
Highlights
Manganese is an essential micronutrient in the body; chronic overexposure can cause extrapyramidal dysfunction, such as Parkinson’s disease (PD), widely referred to as manganism [1]
Excitatory amino acid carrier 1 (EAAC1) is a transporter that is expressed on neurons, which mediates the transport of Glu and cysteine and plays an important role in GSH synthesis
The immunofluorescent intensity of EAAC1 in the 100, 200, and 400 μM MnCl2 groups decreased significantly compared to the untreated group (p < 0 01; p < 0 01; p < 0 01), especially in the 400 μM MnCl2 group where there was an overwhelming reduction of EAAC1 expression
Summary
Manganese is an essential micronutrient in the body; chronic overexposure can cause extrapyramidal dysfunction, such as Parkinson’s disease (PD), widely referred to as manganism [1]. The level of environmental Mn pollution in China is quite high. According to the Chinese Bulletin of Environmental Status in 2016, which is published by the Ministry of Ecology and Environment of People’s Republic of China, Mn levels heavily exceeded drinking water sanitary standard in groundwater and tap water in China, and the risk of water pollution in China involves 18 provinces or areas and affects nearly 310 million people [2]. The neurodegenerative mechanisms caused by Mn are related to dopamine (DA) system
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