Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress.
Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress.
复制标题
硫化氢供体对抗氧化应激的神经保护作用的不同机制
DOI：
10.1016/j.neuint.2013.04.001
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发表时间：
2013-06
影响因子：
4.2
通讯作者：
Cheng J
中科院分区：
文献类型：
--
作者：
Jia J;Xiao Y;Wang W;Qing L;Xu Y;Song H;Zhen X;Ao G;Alkayed NJ;Cheng J
本研究探讨了缓释有机硫化氢供体是否通过与无机供体相同的机制来保护神经元免受氧化应激。通过用谷氨酸诱导神经元细胞系HT 22中的氧化应激，我们研究了有机供体：ADT-OH [5-（4-羟基苯基）-3H-1，2-二硫杂环戊烯-3-基]（用于合成缓释硫化氢供体的最广泛使用的部分）和ADT（ADT-OH的甲基衍生物）的保护机制。有机供体比无机供体硫氢化钠（NaHS）更有效地保护HT 22细胞免受谷氨酸毒性。与之前的出版物一致，NaHS部分恢复了谷氨酸耗尽型谷胱甘肽（GSH）水平，保护HT 22免受过氧化氢（H2 O2）诱导的直接自由基损伤，NaHS保护作用被KATP通道阻滞剂格列本脲消除。然而，ADT和ADT-OH均未增强谷氨酸耗竭的GSH水平或保护HT 22免受H2 O2诱导的氧化应激。格列本脲可消除NaHS对氧化应激的神经保护作用，但不会阻断ADT和ADT-OH对谷氨酸诱导的氧化应激的神经保护作用。出乎意料的是，我们发现谷氨酸诱导AMPK活化，并且化合物C（一种公认的AMPK抑制剂）显著保护HT 22免受谷氨酸诱导的氧化应激，这表明AMPK活化有助于氧化谷氨酸毒性。有趣的是，所有的硫化氢供体，包括NaHS，显着衰减谷氨酸诱导的AMPK激活。然而，在氧化性谷氨酸毒性下，化合物C仅增加用NaHS处理的HT 22细胞的活力，但不进一步增加ADT和ADT-OH神经保护。因此，抑制AMPK活化可能有助于ADT和ADT-OH神经保护作用。总之，硫化氢供体通过不同的机制发挥作用，赋予神经保护作用，以对抗氧化毒性，抑制AMPK活化是有机硫化氢供体的神经保护作用对抗氧化毒性的可能机制。
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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