Protective Effects of S-Nitrosoglutathione Against Neurotoxicity of Amyloid Beta-Peptides in Fetal Rat Cortical Cultures

• Main Authors: Tzyh-Chwen Ju, 朱自淳
• Other Authors: Dean-I Yang
• Format: Others
• Language: en_US
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/39601606029216110142

碩士 === 慈濟大學 === 神經科學研究所 === 93 === Amyloid b-peptide (Ab) is a major constituent of senile plaques in the brains of Alzheimer’s disease (AD) patients. The molecular mechanism underlying AD pathogenesis remains to be fully delineated but may involve heightened oxidative stress as a result of Ab exposure. The sphingomyelin/ceramide pathway is a ubiquitous and evolutionarily conserved signal transduction system linking specific cell surface receptors and environmental stresses to nucleus. We have previously demonstrated ceramide production secondary to Ab-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 "Ab → nSMase → ceramide → free radical → cell death" pathway in primary culture of fetal rat cortical neurons. We also provided experimental evidence showing that S-nitrosoglutathione (GSNO), a potent endogenous antioxidant derived from interaction between nitric oxide (NO) and glutathione, caused dose-dependent protective effects against Ab/ceramide neurotoxicity via inhibition of caspase activation and production of reactive oxygen species (ROS). This GSNO-mediated neuroprotection appears to involve activation of cGMP-dependent protein kinase (PKG), phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK). The cGMP/PKG pathway involved induction of thioredoxin and bcl-2 that were beneficial to cortical neurons in antagonizing Ab/ceramide toxicity. Consistently, exogenous application of thioredoxin exerts remarkable neuroprotective efficacy in our experimental paradigm. Activation of the PI3K pathway resulted in phosphorylation of Bad proteins. Results derived from the present study establish a neuroprotective role of GSNO, an endogenous NO carrier, against Ab toxicity via multiple signaling pathways. A novel regimen for AD therapy directed at manipulations of GSNO metabolism may be envisioned.