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Fluoxetine and Riluzole Mitigates Manganese-Induced Disruption of Glutamate Transporters and Excitotoxicity via Ephrin-A3/GLAST-GLT-1/Glu Signaling Pathway in Striatum of Mice

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Abstract

Manganese (Mn) is an essential element required for many biological processes and systems in the human body. Mn intoxication increases brain glutamate (Glu) levels causing neuronal damage. Recent studies have reported that ephrin-A3 regulates this glutamate transporter. However, none has explored the role of this crucial molecule in Mn-induced excitotoxicity. The present study investigated whether ephrin-A3/GLAST-GLT-1/Glu signaling pathway participates in Mn-induced excitotoxicity using astrocytes and Kunming mice. The mechanisms were explored using fluoxetine (ephrin-A3 inhibitor) and riluzole (a Glu release inhibitor). Firstly, we demonstrated that Mn exposure (500 μM or 50 mg/kg MnCl2) significantly increased Mn, ephrin-A3, and Glu levels, and inhibited Na+-K+ ATPase activity, as well as mRNA and protein levels of GLAST and GLT-1. Secondly, we found that astrocytes and mice pretreated with fluoxetine (100 μM or 15 mg/kg) and riluzole (100 μM or 32 μmol/kg) prior to Mn exposure had lower ephrin-A3 and Glu levels, but higher Na+-K+ ATPase activity, expression levels of GLAST and GLT-1 than those exposed to 500 μM or 50 mg/kg MnCl2. Moreover, the morphology of cells and the histomorphology of mice striatum were injured. Results showed that pretreatment with fluoxetine and riluzole attenuated the Mn-induced motor dysfunctions. Together, these results suggest that the ephrin-A3/GLAST-GLT-1/Glu signaling pathway participates in Mn-induced excitotoxicity, and fluoxetine and riluzole can mitigate the Mn-induced excitotoxicity in mice brain.

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  • 14 September 2020

    The original article contains mistake. Figure 3d and Figure 3e were repeated.

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Acknowledgments

We would like to acknowledge Hui Yuan, Fengdi Wu, Minghui Li, Xianchao Du, Haiying Wang, Bingchen Liu, Lei Zhang, Shuang Wang, and Xuda Liu for their valuable advices.

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All data generated or analyzed during this study are included in this published article.

Funding

We gratefully acknowledge the funding from the National Key Research and Development Project of China (Grant No. 521/2600019004), the Basic Research Fund of Young Program of Higher Education of Liaoning Province (Grant No. QNK201735), the National Natural Science Foundation of China (Grant No. 81302406), and the Funds for Distinguished Young Scientists in School of Public Health, China Medical University.

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  1. Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People’s Republic of China

    Zhipeng Qi, Xinxin Yang, Yanqi Sang, Yanan Liu, Jiashuo Li, Bin Xu, Wei Liu, Miao He, Zhaofa Xu, Yu Deng & Jinghai Zhu

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Each author substantially contributed to the article. Zhipeng Qi, conception and design and drafting the article; Xinxin Yang, Yanqi Sang, Yanan Liu, Jiashuo Li, Bin Xu, Wei Liu, Miao He, and Zhaofa Xu, revising the manuscript; and Yu Deng and Jinghai Zhu, conception and design, revising it critically for important intellectual content, and final approval of the version to be published. All authors read and approved the final manuscript.

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Qi, Z., Yang, X., Sang, Y. et al. Fluoxetine and Riluzole Mitigates Manganese-Induced Disruption of Glutamate Transporters and Excitotoxicity via Ephrin-A3/GLAST-GLT-1/Glu Signaling Pathway in Striatum of Mice. Neurotox Res 38, 508–523 (2020). https://doi.org/10.1007/s12640-020-00209-w

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