Protective effects of S-nitrosoglutathione against amyloid β-peptide neurotoxicity
Protective effects of S-nitrosoglutathione against amyloid β-peptide neurotoxicity
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DOI：
10.1016/j.freeradbiomed.2004.12.019
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发表时间：
2005-04-01
影响因子：
7.4
通讯作者：
Yang, DI
中科院分区：
文献类型：
--
作者：
Ju, TC;Chen, SD;Yang, DI
淀粉样β肽（A β）是阿尔茨海默病（AD）患者脑内老年斑的主要成分。我们先前已经证明了神经酰胺的产生继发于A β诱导的脑内皮细胞和少突胶质细胞中性鞘磷脂酶（nSMase）的激活，这可能有助于AD进展过程中的细胞损伤。在本研究中，我们首先在原代培养的胎鼠皮层神经元中建立了“A β-> nSMase ->神经酰胺->自由基->细胞死亡”通路。我们还提供了实验证据，表明S-亚硝基谷胱甘肽（GSNO），一种有效的内源性抗氧化剂，来自一氧化氮（NO）和谷胱甘肽之间的相互作用，通过抑制caspase激活和活性氧（ROS）的产生，对A β/神经酰胺神经毒性产生剂量依赖性保护作用。这种GSNO介导的神经保护似乎涉及cGMP依赖性蛋白激酶（PKG）、磷脂酰肌醇3-激酶（PI 3 K）和细胞外信号调节激酶（ER-K）的激活。cGMP/PKG通路的激活诱导了硫氧还蛋白和Bcl-2的表达，这有利于皮质神经元拮抗A β/神经酰胺毒性。因此，外源性应用硫氧还蛋白在我们的实验范式中具有显著的神经保护作用。来自本研究的结果建立了GSNO（一种内源性NO载体）通过多种信号传导途径对A β毒性的神经保护作用。(c)2004爱思唯尔公司All rights reserved.
Amyloid beta-peptide (A beta) is a major constituent of senile plaques in the brains of Alzheimer's disease (AD) patients. We have previously demonstrated ceramide production secondary to A beta-induced activation of neutral sphingomyelinase (nSMase) in cerebral endothelial cells and oligodendrocytes, which may contribute to cellular injury during progression of AD. In this study, we first established the "A beta -> nSMase -> ceramide -> free radical -> cell death" pathway in primary cultures of fetal rat cortical neurons. We also provided experimental evidence showing that S-nitrosoglutathione (GSNO), a potent endogenous antioxidant derived from the interaction between nitric oxide (NO) and glutathione, caused dose-dependent protective effects against A beta/ceramide neurotoxicity via inhibition of caspase activation and production of reactive oxygen species (ROS). This GSNO-mediated neuroprotection appeared to involve activation of cGMP-dependent protein kinase (PKG), phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ER-K). Activation of the cGMP/PKG pathway induced expression of thioredoxin and Bcl-2 that were beneficial to cortical neurons in antagonizing A beta/ceramide toxicity. Consistently, exogenous application of thioredoxin exerted remarkable neuroprotective efficacy in our experimental paradigm. Results derived from the present study establish a neuroprotective role of GSNO, an endogenous NO carrier, against A beta toxicity via multiple signaling pathways. (c) 2004 Elsevier Inc. All rights reserved.