Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress

Jia Jia, Yunqi Xiao, Wei Wang, Lina Qing, Yinxiu Xu, Heng Song, Xuechu Zhen, Guizhen Ao, Nabil J. Alkayed, Jian Cheng

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

This study investigated whether slow-releasing organic hydrogen sulfide donors act through the same mechanisms as those of inorganic donors to protect neurons from oxidative stress. By inducing oxidative stress in a neuronal cell line HT22 with glutamate, we investigated the protective mechanisms of the organic donors: ADT-OH [5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione], the most widely used moiety for synthesizing slow-releasing hydrogen sulfide donors, and ADT, a methyl derivative of ADT-OH. The organic donors were more potent than the inorganic donor sodium hydrogensulfide (NaHS) in protecting HT22 cells against glutamate toxicity. Consistent with previous publications, NaHS partially restored glutamate-depleted glutathione (GSH) levels, protected HT22 from direct free radical damage induced by hydrogen peroxide (H2O2), and NaHS protection was abolished by a KATP channel blocker glibenclamide. However, neither ADT nor ADT-OH enhanced glutamate-depleted GSH levels or protected HT22 from H2O2-induced oxidative stress. Glibenclamide, which abolished NaHS neuroprotection against oxidative stress, did not block ADT and ADT-OH neuroprotection against glutamate-induced oxidative stress. Unexpectedly, we found that glutamate induced AMPK activation and that compound C, a well-established AMPK inhibitor, remarkably protected HT22 from glutamate-induced oxidative stress, suggesting that AMPK activation contributed to oxidative glutamate toxicity. Interestingly, all hydrogen sulfide donors, including NaHS, remarkably attenuated glutamate-induced AMPK activation. However, under oxidative glutamate toxicity, compound C only increased the viability of HT22 cells treated with NaHS, but did not further increase ADT and ADT-OH neuroprotection. Thus, suppressing AMPK activation likely contributed to ADT and ADT-OH neuroprotection. In conclusion, hydrogen sulfide donors acted through differential mechanisms to confer neuroprotection against oxidative toxicity and suppressing AMPK activation was a possible mechanism underlying neuroprotection of organic hydrogen sulfide donors against oxidative toxicity.

Original languageEnglish (US)
Pages (from-to)1072-1078
Number of pages7
JournalNeurochemistry International
Volume62
Issue number8
DOIs
StatePublished - Jun 1 2013

    Fingerprint

Keywords

  • AMPK
  • Hydrogen sulfide donors
  • Neuroprotection
  • Oxidative stress

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this