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Melatonin Inhibits Manganese-Induced Motor Dysfunction and Neuronal Loss in Mice: Involvement of Oxidative Stress and Dopaminergic Neurodegeneration

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Abstract

Excessive manganese (Mn) induces oxidative stress and dopaminergic neurodegeneration. However, the relationship between them during Mn neurotoxicity has not been clarified. The purpose of this study was to investigate the probable role of melatonin (MLT) against Mn-induced motor dysfunction and neuronal loss as a result of antagonizing oxidative stress and dopaminergic neurodegeneration. Mice were randomly divided into five groups as follows: control, MnCl2, low MLT + MnCl2, median MLT + MnCl2, and high MLT + MnCl2. Administration of MnCl2 (50 mg/kg) for 2 weeks significantly induced hypokinesis, dopaminergic neurons degeneration and loss, neuronal ultrastructural damage, and apoptosis in the substantia nigra and the striatum. These conditions were caused in part by the overproduction of reactive oxygen species, malondialdehyde accumulation, and dysfunction of the nonenzymatic (GSH) and enzymatic (GSH-Px, superoxide dismutase, quinone oxidoreductase 1, glutathione S-transferase, and glutathione reductase) antioxidative defense systems. Mn-induced neuron degeneration, astrocytes, and microglia activation contribute to the changes of oxidative stress markers. Dopamine (DA) depletion and downregulation of DA transporter and receptors were also found after Mn administration, this might also trigger motor dysfunction and neurons loss. Pretreatment with MLT prevented Mn-induced oxidative stress and dopaminergic neurodegeneration and inhibited the interaction between them. As a result, pretreatment with MLT significantly alleviated Mn-induced motor dysfunction and neuronal loss. In conclusion, Mn treatment resulted in motor dysfunction and neuronal loss, possibly involving an interaction between oxidative stress and dopaminergic neurodegeneration in the substantia nigra and the striatum. Pretreatment with MLT attenuated Mn-induced neurotoxicity by means of its antioxidant properties and promotion of the DA system.

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Acknowledgments

The grants from the National Natural Science Foundation of China (No. 81302406) and the Specialized Research Fund of New Teachers for the Doctoral Program of Higher Education of China (20112104120017) supported this work financially.

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  1. Department of Environmental Health, School of Public Health, China Medical University, North 2nd Road 92, Heping ward, Shenyang, Liaoning, 110001, People’s Republic of China

    Yu Deng, Congcong Jiao, Bin Xu, Yuehui Li, Wei Liu & Zhaofa Xu

  2. Department of School Health Supervision, Institute of Shenyang Health Inspection, Shenyang, 110001, People’s Republic of China

    Chao Mi

  3. Department of Infection Management, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110001, People’s Republic of China

    Fei Wang

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  1. Yu Deng
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Deng, Y., Jiao, C., Mi, C. et al. Melatonin Inhibits Manganese-Induced Motor Dysfunction and Neuronal Loss in Mice: Involvement of Oxidative Stress and Dopaminergic Neurodegeneration. Mol Neurobiol 51, 68–88 (2015). https://doi.org/10.1007/s12035-014-8789-3

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  • DOI: https://doi.org/10.1007/s12035-014-8789-3

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