Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic cell death in rat hippocampal neurons
Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic cell death in rat hippocampal neurons
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DOI：
10.1016/j.biocel.2007.07.019
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发表时间：
2008-01-01
影响因子：
4
通讯作者：
Arnicarelli, Fernanda
中科院分区：
文献类型：
--
作者：
Di Loreto, Silvia;Zimmitti, Vincenzo;Arnicarelli, Fernanda
众所周知，海马体在学习和记忆中起着至关重要的作用。最近的文献数据表明，老年人或糖尿病患者常见的认知问题可能与毒性α-乙醛（如甲基乙二醛）的蓄积有关。因此，这是可能的，甲基乙二醛可能是，至少在部分，负责认知功能的损害，和知识的机制，通过这种化合物elaborate神经元毒性可能是有用的发展可能的治疗strategies.We以前报道了一个高的敏感性，海马神经元甲基乙二醛，通过氧化依赖性机制。在本研究中，我们扩展我们的调查的分子机制，甲基乙二醛毒性的基础上，专注于可能的影响，表达和活性的glycoproteinases，其主要解毒酶，谷胱甘肽过氧化物酶，以及还原型谷胱甘肽的水平。我们还研究了甲基乙二醛诱导的脑源性神经营养因子和促炎细胞因子的调节，结果表明，甲基乙二醛引起还原型谷胱甘肽的急剧消耗，并显着抑制谷胱甘肽酶和谷胱甘肽过氧化物酶的活性。此外，甲基乙二醛治疗似乎影响炎症细胞因子和生存因子的表达。总之，我们的研究结果表明，甲基乙二醛诱导的神经毒性发生通过解毒途径的障碍和还原型谷胱甘肽的消耗。这反过来又引发了广泛的凋亡性细胞死亡，通过线粒体和Fas受体途径的会聚发生。(c)2007爱思唯尔有限公司保留所有权利。
The hippocampus is known to play a crucial role in learning and memory. Recent data from literature show that cognitive problems, common to aged or diabetic patients, may be related to accumulation of toxic alpha-oxoaldehydes such as methylglyoxal. Thus, it is possible that methylglyoxal could be, at least in part, responsible for the impairment of cognitive functions, and the knowledge of the mechanisms through which this compound elicits neuronal toxicity could be useful for the development of possible therapeutic strategies.We previously reported a high susceptibility of hippocampal neurons to methylglyoxal, through an oxidation-dependent mechanism. In the present study, we extend our investigation on the molecular mechanisms which underlie methylglyoxal toxicity, focusing on possible effects on expression and activity of glyoxalases, its main detoxifying enzymes, and glutathione peroxidase, as well as on the levels of reduced glutathione. We also investigate methylglyoxal-induced modulation of brain derived neurotrophic factor and proinflammatory cytokines.Our results show that methylglyoxal causes a dramatic depletion of reduced glutathione and a significant inhibition of both glyoxalase and glutathione peroxidase activities. Furthermore, methylglyoxal treatment seems to affect the expression of inflammatory cytokines and survival factors.In conclusion, our findings suggest that methylglyoxal-induced neurotoxicity occurs through the impairment of detoxification pathway and depletion of reduced glutathione. This, in turn, triggers widespread apoptotic cell death, occurring through the convergence of both mitochondrial and Fas-receptor pathways. (c) 2007 Elsevier Ltd. All rights reserved.