title: Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress.
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.
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Xiao
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Lina
authors.initials: L
authors.lastname: Qing
authors.forename: Yinxiu
authors.initials: Y
authors.lastname: Xu
authors.forename: Heng
authors.initials: H
authors.lastname: Song
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
authors.forename: Guizhen
authors.initials: G
authors.lastname: Ao
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
authors.forename: Jian
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006862:Hydrogen Sulfide / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation
chemical_list: D018696:Neuroprotective Agents; D000263:Adenylate Kinase; D006862:Hydrogen Sulfide