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 Alkayed, Jian Cheng

Research output: Contribution to journalArticle

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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 2013

Fingerprint

Hydrogen Sulfide
Glutamic Acid
Oxidative Stress
AMP-Activated Protein Kinases
Glyburide
Neuroprotection
KATP Channels
Hydrogen Peroxide
Free Radicals
Glutathione
sodium bisulfide
Cell Survival
Sodium
Neurons
Cell Line

Keywords

  • AMPK
  • Hydrogen sulfide donors
  • Neuroprotection
  • Oxidative stress

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress. / Jia, Jia; Xiao, Yunqi; Wang, Wei; Qing, Lina; Xu, Yinxiu; Song, Heng; Zhen, Xuechu; Ao, Guizhen; Alkayed, Nabil; Cheng, Jian.

In: Neurochemistry International, Vol. 62, No. 8, 06.2013, p. 1072-1078.

Research output: Contribution to journalArticle

Jia, Jia ; Xiao, Yunqi ; Wang, Wei ; Qing, Lina ; Xu, Yinxiu ; Song, Heng ; Zhen, Xuechu ; Ao, Guizhen ; Alkayed, Nabil ; Cheng, Jian. / Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress. In: Neurochemistry International. 2013 ; Vol. 62, No. 8. pp. 1072-1078.
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AU - Jia, Jia

AU - Xiao, Yunqi

AU - Wang, Wei

AU - Qing, Lina

AU - Xu, Yinxiu

AU - Song, Heng

AU - Zhen, Xuechu

AU - Ao, Guizhen

AU - Alkayed, Nabil

AU - Cheng, Jian

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N2 - 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.

AB - 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.

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KW - Neuroprotection

KW - Oxidative stress

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