Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo.
Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo.
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DOI：
10.1016/j.redox.2022.102484
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发表时间：
2022-11
期刊：
影响因子：
11.4
通讯作者：
More, Swati S.
中科院分区：
文献类型：
--
作者：
Rao, Swetha Pavani;Xie, Wei;Kwon, Ye In Christopher;Juckel, Nicholas;Xie, Jiashu;Dronamraju, Venkateshwara Rao;Vince, Robert;Lee, Michael K.;More, Swati S.
氧化应激和炎症的增加与阿尔茨海默病的发病机制有关。在临床前研究中，用硫化氢(H_2S)和硫化氢供体(如氢化钠(NASH))治疗可以减少氧化应激，然而这种治疗的临床益处是相当模糊的。这在一定程度上是由于硫化氢供体的稳定性和生物利用度较差，需要与剂量限制毒性相关的不切实际的大剂量。在这里，我们鉴定了一种生物可用的3-硫代丙酮酸前药，磺酸甘油，它能够作为大脑中H_2S生物合成酶之一的3-硫代丙酮酸硫转移酶(3MST)的牺牲氧化还原底物。磺酸根通过3MST途径释放H_2S，能够减轻氧化损伤和Aβ1-42肽的毒性。当给予有症状的转基因AD小鼠模型(APP/PS1；7个月和12个月)和脑室注射Aβ1-42肽的小鼠时，磺胺根能够通过恢复3MST功能来逆转AD病理的氧化和神经炎性后果。定量神经病理学分析证实，该化合物对淀粉样斑块负荷和脑炎性标志物具有显著的疾病改善作用。更重要的是，磺胺治疗减轻了这些小鼠的进行性神经变性，这从蓝斑TH+神经元的恢复中可见一斑。这项研究证明了一个以前未知的概念，即在大脑中补充3MST功能可能是治疗AD的可行方法。最后，将磺胺类药物作为未来药物开发努力的一种有前途的AD治疗方法的潜力带到了聚光灯下。在有症状的APP/PS1小鼠中发现3MST功能受损。补充磺酸根可恢复AD小鼠脑内3MST活性。磺酸可减轻大脑氧化应激、神经炎症和神经退行性变。恢复3MST功能是应对AD病理的一种可行策略。
Increased oxidative stress and inflammation are implicated in the pathogenesis of Alzheimer's disease. Treatment with hydrogen sulfide (H2S) and H2S donors such as sodium hydrosulfide (NaSH) can reduce oxidative stress in preclinical studies, however clinical benefits of such treatments are rather ambiguous. This is partly due to poor stability and bioavailability of the H2S donors, requiring impractically large doses that are associated with dose-limiting toxicity. Herein, we identified a bioavailable 3-mercaptopyruvate prodrug, sulfanegen, which is able to pose as a sacrificial redox substrate for 3-mercaptopyruvate sulfurtransferase (3MST), one of the H2S biosynthetic enzymes in the brain. Sulfanegen is able to mitigate toxicity emanating from oxidative insults and the Aβ1-42 peptide by releasing H2S through the 3MST pathway. When administered to symptomatic transgenic mouse model of AD (APP/PS1; 7 and 12 months) and mice that were intracerebroventricularly administered with the Aβ1-42 peptide, sulfanegen was able to reverse oxidative and neuroinflammatory consequences of AD pathology by restoring 3MST function. Quantitative neuropathological analyses confirmed significant disease modifying effect of the compound on amyloid plaque burden and brain inflammatory markers. More importantly, sulfanegen treatment attenuated progressive neurodegeneration in these mice, as evident from the restoration of TH+ neurons in the locus coeruleus. This study demonstrates a previously unknown concept that supplementation of 3MST function in the brain may be a viable approach for the management of AD. Finally, brought into the spotlight is the potential of sulfanegen as a promising AD therapeutic for future drug development efforts. Compromised 3MST function is discovered in symptomatic APP/PS1 mice. Supplementation with sulfanegen restores 3MST activity in AD mouse brain. Sulfanegen attenuated brain oxidative stress, neuroinflammation and neurodegeneration. Restoration of 3MST function is a viable strategy to tackle AD pathology.
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DOI：
10.1002/alz.12305
发表时间：
2021-08
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Disbrow E;Stokes KY;Ledbetter C;Patterson J;Kelley R;Pardue S;Reekes T;Larmeu L;Batra V;Yuan S;Cvek U;Trutschl M;Kilgore P;Alexander JS;Kevil CG
通讯作者：
Kevil CG
影响因子：
4.7
作者：
Hu, Li-Fang;Wong, Peter T. -H.;Bian, Jin-Song
通讯作者：
Bian, Jin-Song
影响因子：
4.8
作者：
Kimura, Y;Kimura, H
通讯作者：
Kimura, H
影响因子：
2.9
作者：
Kartha, Reena V.;Zhou, Jie;Schroeder, Henning
通讯作者：
Schroeder, Henning
DOI：
10.1016/s0006-291x(02)00422-9
发表时间：
2002-05-24
影响因子：
3.1
作者：
Eto, K;Asada, T;Kimura, H
通讯作者：
Kimura, H