Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress

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• 作者：Jia Jia^a ; ^b ; ^c ; ¹ ; Yunqi Xiao^c ; ¹ ; Wei Wang^a ; ¹ ; Lina Qing^c ; Yinxiu Xu^c ; Heng Song^d ; Xuechu Zhen^a ; Guizhen Ao^d ; ^{aoguizhen@suda.edu.cn} ; Nabil J. Alkayed^e ; Jian Cheng^c ; ^{jiancheng8@hotmail.com}
• 关键词：ADT-OH ; 5-(4-hydroxyphenyl)-3H-1/2-dithiole-3-thione ; ADT ; 5-(4-methoxyphenyl)-3H-1/2-dithiole-3-thione ; AMPK ; AMP-activated protein kinase ; GSH ; glutathione ; H2O2 ; hydrogen peroxide ; KATP channel ; ATP-sensitive potassium channel ; NaHS ; sodium hydrogensul
• 刊名：Neurochemistry International
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：62
• 期：8
• 页码：1072-1078
• 全文大小：809 K

文摘

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 K_ATP 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.