In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer's disease and other oxidative stress-related neurodegenerative disorders
In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer's disease and other oxidative stress-related neurodegenerative disorders
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DOI：
10.1016/j.freeradbiomed.2006.09.002
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发表时间：
2006-12-01
影响因子：
7.4
通讯作者：
Butterfield, D. Allan
中科院分区：
文献类型：
--
作者：
Ansari, Mubeen Ahmad;Joshi, Gururaj;Butterfield, D. Allan
三环癸-9-基-黄原酸酯（D 609）具有体内和体外抗氧化特性。D 609模拟谷胱甘肽（GSH），具有游离巯基，氧化后形成二硫化物。所得的二黄原酸盐是谷胱甘肽还原酶的底物，再生D 609。最近的研究还表明，D 609保护脑在体内和神经元培养物在体外对潜在的阿尔茨海默病（AD）的致病因素，A β（1-42）诱导的氧化应激和细胞毒性。线粒体是重要的细胞器，具有促凋亡因子蛋白和抗凋亡因子蛋白。本研究进行测试的假设，腹腔注射D 609将提供对自由基诱导的神经保护，在体外细胞凋亡介导的。在腹腔内（ip）注射D 609后1 h，从沙鼠中分离脑线粒体，随后在体外用氧化剂Fe 2 +/H2 O2（羟基自由基）、2，2-偶氮双-（2-脒基丙烷）二盐酸盐（AAPH，烷氧基和过氧基自由基）和AD相关淀粉样β-肽1-42 [A β（1-42）]处理。从先前用D 609 ip注射的沙鼠中分离的脑线粒体在体外经受这些氧化应激诱导剂，与从盐水注射的沙鼠中分离的经氧化剂处理的脑线粒体相比，显示蛋白质羰基、蛋白质结合的羟基壬烯醛[脂质过氧化产物]、3-硝基酪氨酸和细胞色素c释放水平显著降低。D 609处理显著维持氧化剂处理的线粒体中的GSH/GSSG比率。谷胱甘肽S-转移酶，谷胱甘肽过氧化物酶，谷胱甘肽还原酶的活性增加，在脑分离D 609注射沙鼠是一致的概念，D 609的行为像谷胱甘肽。这些抗凋亡的研究结果进行了讨论，参考潜在的使用这种大脑接触谷胱甘肽模拟物在治疗氧化应激相关的神经退行性疾病，包括AD。(c)2006年爱思唯尔公司All rights reserved.
Tricyclodecan-9-yl-xanthogenate (D609) has in vivo and in vitro antioxidant properties. D609 mimics glutathione (GSH) and has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies have also shown that D609 protects brain in vivo and neuronal cultures in vitro against the potential Alzheimer's disease (AD) causative factor, A beta(1-42)-induced oxidative stress and cytotoxicity. Mitochondria are important organelles with both pro- and antiapoptotic factor proteins. The present study was undertaken to test the hypothesis that intraperitoneal injection of D609 would provide neuroprotection against free radical-induced, mitochondria-mediated apoptosis in vitro. Brain mitochondria were isolated from gerbils I h post injection intraperitoneally (ip) with D609 and subsequently treated in vitro with the oxidants Fe2+/H2O2 (hydroxyl free radicals), 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH, alkoxyl and peroxyl free radicals), and AD-relevant amyloid beta-peptide 1-42 [A beta(1-42)]. Brain mitochondria isolated from the gerbils previously injected ip with D609 and subjected to these oxidative stress inducers, in vitro, showed significant reduction in levels of protein carbonyls, protein-bound hydroxynonenal [a lipid peroxidation product], 3-nitrotyrosine, and cytochrome c release compared to oxidant-treated brain mitochondria isolated from saline-injected gerbils. D609 treatment significantly maintains the GSH/GSSG ratio in oxidant-treated mitochondria. Increased activity of glutathione S-transferase, glutathione peroxidase, and glutathione reductase in brain isolated from D609-injected gerbils is consistent with the notion that D609 acts like GSH. These antiapoptotic findings are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders, including AD. (c) 2006 Elsevier Inc. All rights reserved.