Polysulfide protects midbrain dopaminergic neurons from MPP + -induced degeneration via enhancement of glutathione biosynthesis

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Abstract

Polysulfides are endogenous sulfur-containing molecular species that may regulate various cellular functions. Here we examined the effect of polysulfides exogenously applied to rat midbrain slice cultures, to address their potential neuroprotective actions. Na 2 S 3 at concentrations of 10 μM or higher prevented 1-methyl-4-phenylpyridinium (MPP + )-induced loss of dopaminergic neurons. Na 2 S 4 at 10 μM also protected dopaminergic neurons from MPP + cytotoxicity, whereas Na 2 S and Na 2 S 2 at the same concentration had no significant effect. We also found that Na 2 S 3 (10 μM) prevented MPP + -induced increase in intracellular reactive oxygen species as detected by 2′,7′-dichlorofluorescein fluorescence. In addition, the protective effect of Na 2 S 3 was abolished by L-buthionine sulfoximine, an inhibitor of glutathione synthesis. In cellular models of neurons (SH-SY5Y cells) and glial cells (C6 cells), Na 2 S 3 (30 and 100 μM) increased expression of mRNAs encoding the subunits of glutamate cysteine ligase, the rate-limiting enzyme for glutathione biosynthesis. Consistently, the cellular content of total glutathione was increased by Na 2 S 3 , and the effect was more prominent in SH-SY5Y cells than in C6 cells. These results suggest that polysulfides are efficient neuroprotectants superior to monosulfur species such as H 2 S and HS − , and that the neuroprotective effect of polysulfides is mediated by upregulation of glutathione biosynthesis.

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Takahashi, S., Hisatsune, A., Kurauchi, Y., Seki, T., & Katsuki, H. (2018). Polysulfide protects midbrain dopaminergic neurons from MPP + -induced degeneration via enhancement of glutathione biosynthesis. Journal of Pharmacological Sciences, 137(1), 47–54. https://doi.org/10.1016/j.jphs.2018.04.004

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