Neuroprotective effect of epigallocatechin-3-gallate against β-amyloid-induced oxidative and nitrosative cell death via augmentation of antioxidant defense capacity
Neuroprotective effect of epigallocatechin-3-gallate against β-amyloid-induced oxidative and nitrosative cell death via augmentation of antioxidant defense capacity
复制标题
DOI：
10.1007/s12272-009-1609-z
复制
发表时间：
2009-06-01
影响因子：
6.7
通讯作者：
Jang, Jung-Hee
中科院分区：
文献类型：
--
作者：
Kim, Chang-Yul;Lee, Chan;Jang, Jung-Hee
β-淀粉样蛋白 (Aβ) 肽是老年斑的主要成分，被认为在阿尔茨海默病 (AD) 的发展和神经发病机制中发挥着至关重要的作用。越来越多的体外和体内研究数据表明，Aβ 诱导的神经元和神经胶质细胞损伤是通过亚硝化和氧化应激介导的。因此，最近的研究重点是寻找饮食和草药操作来防止 Aβ 诱导的氧化和/或亚硝化细胞死亡。表没食子儿茶素-3-没食子酸酯 (EGCG) 是这些候选物之一，是绿茶中存在的主要多酚化合物，据报道具有有效的抗氧化和抗炎特性。在本研究中，我们研究了 EGCG 对 Aβ 诱导的 BV2 小胶质细胞氧化和/或亚硝化细胞死亡的影响。 DNA 片段化、线粒体跨膜电位扰动以及凋亡调节因子 Bcl-2 家族蛋白表达的改变表明，β 处理导致 BV2 细胞凋亡。 EGCG 预处理有效改善了 Aβ 诱导的细胞毒性和促凋亡信号的表现。此外，暴露于Aβ的BV2细胞经历亚硝化应激，表现为诱导型一氧化氮合酶（iNOS）表达增加以及随后产生一氧化氮（NO）和过氧亚硝酸盐，而EGCG预处理可有效抑制这些应激。为了阐明 EGCG 神经保护作用的分子机制，我们研究了具有抗氧化特性的还原型谷胱甘肽 (GSH) 的细胞代谢。 EGCG 处理通过提高 γ-谷氨酰半胱氨酸连接酶 (GCL)（谷胱甘肽生物合成中的限速酶）的 mRNA 表达来强化细胞 GSH 库。这些结果表明，EGCG 可能通过增强细胞抗氧化防御能力和减弱 Aβ 介导的氧化和/或亚硝化细胞死亡，对 AD 患者具有预防和/或治疗潜力。
beta-Amyloid (A beta) peptide, a major component of senile plaques has been regarded to play a crucial role in the development and neuropathogenesis of Alzheimer's disease (AD). Increasing data from in vitro and in vivo studies indicate that A beta-induced damages in neurons and glia are mediated via nitrosative as well as oxidative stress. Therefore, recent researches have been focused on searching for dietary and herbal manipulations to protect against the A beta-induced oxidative and/or nitrosative cell death. Epigallocatechin-3-gallate (EGCG), one of these candidates is a major polyphenolic compound present in green tea and has been reported to exhibit potent antioxidant and anti-inflammatory properties. In the present study, we have investigated the effect of EGCG against A beta-induced oxidative and/or nitrosative cell death in BV2 microglia. A beta treatment led to apoptosis in BV2 cells as revealed by DNA fragmentation, perturbation of mitochondrial transmembrane potential, and alterations in the expression of apoptosis-regulator Bcl-2 family proteins. EGCG pretreatment effectively ameliorated A beta-induced cytotoxicity and manifestation of proapoptotic signals. Furthermore, BV2 cells exposed to A beta underwent nitrosative stress as shown by the increased expression of inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO) and peroxynitrite, which were effectively suppressed by EGCG pretreatment. To elucidate a molecular mechanism underlying the neuroprotective effect of EGCG, we have examined the cellular metabolism of reduced glutathione (GSH) with antioxidant properties. EGCG treatment fortified cellular GSH pool through elevated mRNA expression of gamma-glutamylcysteine ligase (GCL), the rate limiting enzyme in the glutathione biosynthesis. These results suggest that EGCG may have preventive and/or therapeutic potential in AD patients by augmenting cellular antioxidant defense capacity and attenuating A beta-mediated oxidative and/or nitrosative cell death.