Hydrogen sulfide slows down progression of experimental Alzheimer's disease by targeting multiple pathophysiological mechanisms
Hydrogen sulfide slows down progression of experimental Alzheimer's disease by targeting multiple pathophysiological mechanisms
复制标题
DOI：
10.1016/j.nlm.2013.05.006
复制
发表时间：
2013-09-01
影响因子：
2.7
通讯作者：
Guarini, Salvatore
中科院分区：
文献类型：
--
作者：
Giuliani, Daniela;Ottani, Alessandra;Guarini, Salvatore
此前有报道称，阿尔茨海默病（AD）患者脑硫化氢（H2S）合成严重下降，且血浆H2S水平与AD的严重程度呈负相关。在这里，我们广泛研究了H2S供体和富含H2S的水疗水是否能诱导神经保护并减缓AD的进展。采用氢硫化钠（H2S供体）和Tabiano’s spa-water对三种AD实验模型进行了研究。在脑内注射β -淀粉样蛋白（1-40）（A β）或链脲佐菌素诱导的AD大鼠模型以及含有人类转基因APP（Swe）、PS1（M146V）和tau(P301L) （3xTg-AD小鼠）的AD小鼠模型中，短期和长期使用氢硫化钠和/或Tabiano’s spa-water显著保护学习和记忆障碍。行为表现的改善与海马A β斑块的大小和形态图像的保存有关，这在AD大鼠中发现。此外，在接受水疗水治疗的3xTg-AD小鼠中，检测到淀粉样蛋白前体蛋白、早老素-1、A β(1-42)和在Thr181、Ser396和Ser202位点磷酸化的tau蛋白的浓度/磷酸化水平降低，这些蛋白被认为是AD病理生理的中心事件。在3xTg-AD小鼠中，兴奋性毒性引发的氧化应激和亚硝化应激被抵消，大脑皮层中丙二醛和亚硝酸盐水平下降。还发现海马c-jun n端激酶、细胞外信号调节激酶和p38活性降低，这些激酶不仅在tau蛋白磷酸化中起作用，而且在炎症和细胞凋亡中起作用。Tabiano spa水治疗3xTg-AD小鼠海马组织中肿瘤坏死因子- α水平下降，Bcl-2上调，BAX及下游刽子手caspase-3下调，提示Tabiano spa水还具有调节炎症和细胞凋亡的作用。我们的研究结果表明，用H2S供体和Tabiano水疗水以及其他富含H2S含量的水疗水进行适当的治疗，可能是一种通过针对多种病理生理机制来减缓人类AD进展的创新方法。(C) 2013爱思唯尔公司版权所有。
It has been previously reported that brain hydrogen sulfide (H2S) synthesis is severely decreased in Alzheimer's disease (AD) patients, and plasma H2S levels are negatively correlated with the severity of AD. Here we extensively investigated whether treatment with a H2S donor and spa-waters rich in H2S induces neuroprotection and slows down progression of AD. Studies with sodium hydrosulfide (a H2S donor) and Tabiano's spa-water were carried out in three experimental models of AD. Short-term and long-term treatments with sodium hydrosulfide and/or Tabiano's spa-water significantly protected against impairment in learning and memory in rat models of AD induced by brain injection of beta-amyloid(1-40) (A beta) or streptozotocin, and in an AD mouse model harboring human transgenes APP(Swe), PS1(M146V) and tau(P301L) (3xTg-AD mice). The improvement in behavioral performance was associated with hippocampus was size of A beta plaques and preservation of the morphological picture, as found in AD rats. Further, lowered concentration/phosphorylation levels of proteins thought to be the central events in AD pathophysiology, namely amyloid precursor protein, presenilin-1, A beta(1-42) and tau phosphorylated at Thr181, Ser396 and Ser202, were detected in 3xTg-AD mice treated with spa-water. The excitotoxicity-triggered oxidative and nitrosative stress was counteracted in 3xTg-AD mice, as indicated by the decreased levels of malondialdehyde and nitrites in the cerebral cortex. Hippocampus reduced activity of c-jun N-terminal kinases, extracellular signal-regulated kinases and p38, which have an established role not only in phosphorylation of tau protein but also in inflammation and apoptosis, was also found. Consistently, decrease in tumor necrosis factor-alpha level, up-regulation of Bcl-2, and down-regulation of BAX and the downstream executioner caspase-3, also occurred in the hippocampus of 3xTg-AD mice after treatment with Tabiano's spa-water, thus suggesting that it is also able to modulate inflammation and apoptosis. Our findings indicate that appropriate treatments with H2S donors and Tabiano's spa-waters, and may be other spa-waters rich in H2S content, might represent an innovative approach to slow down AD progression in humans by targeting multiple pathophysiological mechanisms. (C) 2013 Elsevier Inc. All rights reserved.