Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells -: protection by carbonyl scavengers
Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells -: protection by carbonyl scavengers
复制标题
DOI：
10.1016/j.neurobiolaging.2006.05.007
复制
发表时间：
2007-07-01
影响因子：
4.2
通讯作者：
Muench, Gerald
中科院分区：
文献类型：
--
作者：
de Arriba, Susana Garcia;Stuchbury, Grant;Muench, Gerald
晚期糖基化终末产物(AGEs)存在于多种神经细胞内蛋白沉积中，如阿尔茨海默病中的神经纤维缠结和帕金森病中的路易小体。在许多活性羰基化合物和AGE前体中，甲基乙二醛最有可能促进细胞内AGE的形成，因为它具有极强的活性，并且不断地由磷酸丙糖降解产生。此外，在病理生理条件下，甲基乙二醛水平增加，例如，当三糖磷酸水平升高时，乙醛酸酶I的表达或活性降低，当乙二醛酶1的速率决定辅助因子还原型谷胱甘肽浓度较低时就是如此。然而，甲基乙二醛对线粒体功能和能量水平的影响还没有详细的研究。在这项研究中，我们发现甲基乙二醛增加了SH-SY5Y神经母细胞瘤细胞内活性氧和乳酸的形成。甲基乙二醛还降低线粒体膜电位和细胞内ATP水平，提示甲基乙二醛的细胞毒性作用可能与甲基乙二醛引起的线粒体完整性丧失有关。甲基乙醛诱导的效应，如ATP耗竭和线粒体功能障碍，可以通过预先与羰基清除剂氨基胍和替尼西坦孵育细胞来预防。在临床背景下，这些化合物不仅可以提供一种有前景的治疗策略来减少细胞内AGE的积累，而且还可以减少二羰基引起的衰老和神经退行性变中能量产生的损害。(C)2006 Elsevier Inc.保留所有权利。
Advanced glycation end products (AGEs) are found in various intraneuronal protein deposits such as neurofibrillary tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease. Among the many reactive carbonyl compounds and AGE precursors, methylglyoxal is most likely to contribute to intracellular AGE formation, since it is extremely reactive and constantly produced by degradation of triosephosphates. Furthermore, methylglyoxal levels increase under pathophysiological conditions, for example, when trisosephosphate levels are elevated, the expression or activity of glyoxalase I is decreased, as is the case when the concentration of reduced glutathione, the rate-determining co-factor of glyoxalase 1, is low. However, the effects of methylglyoxal on mitochondrial function and energy levels have not been studied in detail. In this study, we show that methylglyoxal increases the formation of intracellular reactive oxygen species and lactate in SH-SY5Y neuroblastoma cells. Methylglyoxal also decreases mitochondrial membrane potential and intracellular ATP levels, suggesting that carbonyl stress-induced loss of mitochondrial integrity could contribute to the cytotoxicity of methylglyoxal. The methylglyoxal-induced effects such as ATP depletion and mitochondrial dysfunction can be prevented by pre-incubation of the cells with the carbonyl scavengers aminoguanidine and tenilsetam. In a clinical context, these compounds could not only offer a promising therapeutic strategy to reduce intracellular AGE-accumulation, but also to decrease the dicarbonyl-induced impairment of energy production in aging and neurodegeneration. (C) 2006 Elsevier Inc. All rights reserved.