Mitochondrially targeted vitamin E and vitamin E mitigate ethanol-mediated effects on cerebellar granule cell antioxidant defense systems.
Mitochondrially targeted vitamin E and vitamin E mitigate ethanol-mediated effects on cerebellar granule cell antioxidant defense systems.
复制标题
线粒体靶向维生素 E 和维生素 E 可减轻乙醇介导的对小脑颗粒细胞抗氧化防御系统的影响。
DOI：
10.1016/j.brainres.2005.06.030
复制
发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Heaton,MarietaB
中科院分区：
文献类型：
--
作者：
Siler-Marsiglio,KendraI;Pan,Qun;Paiva,Michael;Madorsky,Irina;Khurana,NilaC;Heaton,MarietaB
乙醇（EtOH）会破坏发育中的神经系统的结构和功能，有时会导致与胎儿酒精综合征（FAS）相关的出生缺陷。动物FAS模型表明，细胞膜过氧化、细胞内氧化剂蓄积和内源性抗氧化酶的抑制导致EtOH的毒性作用。线粒体靶向维生素E（MitoVit E）是维生素E（VE）的一种化学工程形式，旨在在线粒体中积累，已被证明比VE更有效地抑制细胞内氧化剂积累和细胞死亡。在以前的研究中，我们已经表明，在体内，VE减少神经元死亡的EtOH暴露的动物的小脑发育，并在体外，VE防止EtOH暴露的小脑颗粒细胞（CGCs）的凋亡和坏死性死亡。本研究表明，在FAS CGC模型中，1 nM MitoVit E对高达1600 mg/dL的EtOH浓度具有显著的神经保护作用。本研究还表明，在同一模型中，MitoVit E可减轻EtOH诱导的细胞内氧化剂蓄积，并抵消谷胱甘肽过氧化物酶/谷胱甘肽还原酶（GSH-Px/GSSG-R）功能、γ-谷氨酰半胱氨酸合成酶（γ-GCS）蛋白表达和总细胞谷胱甘肽（GSH）水平的抑制。在存在和不存在EtOH的情况下，VE放大γ-GCS（一种执行GSH合成限速步骤的酶）的蛋白质表达水平和总GSH水平。这些结果表明，MitoVit E和VE通过非氧化机制（调节内源性细胞蛋白质）和抗氧化手段改善EtOH毒性。
Ethanol (EtOH) disrupts the structure and function of the developing nervous system, sometimes leading to birth defects associated with fetal alcohol syndrome (FAS). Animal FAS models indicate that cellular membrane peroxidation, intracellular oxidant accumulation, and suppression of endogenous antioxidant enzymes contribute to the toxic effects of EtOH. Mitochondrially targeted vitamin E (MitoVit E), a chemically engineered form of vitamin E (VE) designed to accumulate in the mitochondria, has been shown to inhibit intracellular oxidant accumulation and cell death more effectively than VE. In previous investigations, we have shown that, in vivo, VE reduces neuronal death in the developing cerebellum of EtOH-exposed animals, and, in vitro, VE prevents apoptotic and necrotic death of EtOH-exposed cerebellar granule cells (CGCs). The present investigation shows that, in a FAS CGC model, 1 nM MitoVit E renders significant neuroprotection against EtOH concentrations as high as 1600 mg/dL. The present study also demonstrates that, in this same model, MitoVit E mitigates EtOH-induced accumulation of intracellular oxidants and counteracts suppression of glutathione peroxidase/glutathione reductase (GSH-Px/GSSG-R) functions, protein expression of gamma-glutamylcysteine synthetase (γ-GCS), and total cellular glutathione (GSH) levels. In the presence and absence of EtOH, VE amplifies the protein expression levels of γ-GCS, an enzyme that performs the rate-limiting step for GSH synthesis, and total GSH levels. These results suggest that MitoVit E and VE ameliorate EtOH toxicity through non-oxidant mechanisms–modulations of endogenous cellular proteins–and antioxidant means.