Jang Jung-Hee, Aruoma Okezie I, Jen Ling-Sun, Chung Hae Young, Surh Young-Joon
Laboratory of Biochemistry and Molecular Toxicology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Free Radic Biol Med. 2004 Feb 1;36(3):288-99. doi: 10.1016/j.freeradbiomed.2003.11.005.
Beta-amyloid (Abeta) peptide is the major component of senile plaques and considered to have a causal role in the development and progression of Alzheimer's disease. There has been compelling evidence that Abeta-induced cytotoxicity is mediated through oxidative and/or nitrosative stress. Recently, considerable attention has been focused on dietary manipulation of oxidative and/or nitrosative damage. l-Ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine) is a low-molecular-weight naturally occurring thiol compound of dietary origin that exists in the brain, liver, kidney, erythrocytes, ocular tissues, and seminal fluids of mammals. This water-soluble antioxidant has the ability to scavenge hydroxyl and peroxynitrite radicals as well as activated oxygen species, such as singlet oxygen. In this study, we investigated the effects of EGT on Abeta-induced oxidative and/or nitrosative cell death. Rat pheochromocytoma (PC12) cells treated with Abeta underwent apoptotic death as determined by positive in situ terminal end-labeling (TUNEL staining), decreased mitochondrial transmembrane potential, increased ratio of proapoptotic Bax to antiapoptotic Bcl-XL, elevated caspase-3 activity, and cleavage of poly(ADP-ribose) polymerase. EGT pretreatment attenuated Abeta-induced apoptosis in PC12 cells. Compared to N-acetyl-l-cysteine, which mainly scavenges reactive oxygen species, EGT effectively inhibited Abeta-induced cell death by suppressing peroxynitrite formation and subsequent nitration of protein tyrosine residues. The effects of EGT on the cytotoxicity induced by the nitric oxide donor sodium nitroprusside (SNP) and the peroxynitrite-generating 3-morpholinosydnonimine chlorhydrate (SIN-1) were compared. Whereas EGT significantly protected against SIN-1-mediated cell death, it barely affected the cytotoxicity induced by SNP. Thus EGT may attenuate apoptosis caused by Abeta, preferentially by eliminating peroxynitrite derived from the neurotoxic peptide. The importance of diet-derived antioxidants in the management of Alzheimer's disease and other neurodegenerative disorders is discussed.
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的发生和发展中起因果作用。有确凿证据表明，Aβ诱导的细胞毒性是通过氧化和/或亚硝化应激介导的。最近，相当多的注意力集中在通过饮食控制氧化和/或亚硝化损伤。L-麦角硫因（EGT；2-巯基组氨酸三甲基甜菜碱）是一种低分子量的天然存在的膳食来源硫醇化合物，存在于哺乳动物的脑、肝、肾、红细胞、眼组织和精液中。这种水溶性抗氧化剂能够清除羟基和过氧亚硝酸盐自由基以及活性氧，如单线态氧。在本研究中，我们研究了EGT对Aβ诱导的氧化和/或亚硝化细胞死亡的影响。用Aβ处理的大鼠嗜铬细胞瘤（PC12）细胞发生凋亡死亡，这通过原位末端标记阳性（TUNEL染色）、线粒体跨膜电位降低、促凋亡Bax与抗凋亡Bcl-XL的比例增加、半胱天冬酶-3活性升高以及聚（ADP-核糖）聚合酶的裂解来确定。EGT预处理减轻了Aβ诱导的PC12细胞凋亡。与主要清除活性氧的N-乙酰-L-半胱氨酸相比，EGT通过抑制过氧亚硝酸盐的形成以及随后蛋白质酪氨酸残基的硝化，有效抑制了Aβ诱导的细胞死亡。比较了EGT对一氧化氮供体硝普钠（SNP）和过氧亚硝酸盐生成剂3-吗啉代 sydnonimine盐酸盐（SIN-1）诱导的细胞毒性的影响。虽然EGT显著保护细胞免受SIN-1介导的细胞死亡，但它几乎不影响SNP诱导的细胞毒性。因此，EGT可能通过优先消除神经毒性肽衍生的过氧亚硝酸盐来减轻Aβ引起的凋亡。讨论了膳食来源的抗氧化剂在阿尔茨海默病和其他神经退行性疾病管理中的重要性。
