Fluoxetine and Riluzole Mitigates Manganese-Induced Disruption of Glutamate Transporters and Excitotoxicity via Ephrin-A
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ORIGINAL ARTICLE
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 Zhipeng Qi 1 & Xinxin Yang 1 & Yanqi Sang 1 & Yanan Liu 1 & Jiashuo Li 1 & Bin Xu 1 & Wei Liu 1 & Miao He 1 & Zhaofa Xu 1 & Yu Deng 1 & Jinghai Zhu 1 Received: 31 January 2020 / Revised: 9 April 2020 / Accepted: 14 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Fluoxetine . Manganese . Ephrin-A3 . GLAST . GLT-1 . Excitotoxicity
Introduction Manganese (Mn) is an essential and abundant micronutrient required for normal development and growth. It is a cofactor in enzymatic reactions during synthesis of neurotransmitters and in normal neuronal and glial functions (Karki et al. 2015). However, accumulation of Mn in the brain following chronic exposure to excessive levels of this metal, from either environmental or occupational sources, leads to a parkinsonianlike syndrome, referred to as manganism. Mn accumulates in
* Yu Deng [email protected] * Jinghai Zhu [email protected] 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
the body due to drinking of water containing high levels of the metal (Wasserman et al. 2006) and also from atmospheric Mn (Krachler and Rossipal 2000). Other sources of Mn include Mn
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