The link between lipid peroxidation and manganese induced glutathione depletion

脂质过氧化与锰诱导的谷胱甘肽消耗之间的联系

• 批准号: 7364323
• 负责人: KEITH M ERIKSON
• 金额: $ 20.93万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2011-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364323
• 关键词: Affect; Age; Animals; Antioxidants; Astrocytes; Attenuated; Biochemical; Biological Markers; Bradykinesia; Brain; Brain region; Cell physiology; Cells; Condition; Cultured Cells; Development; Disease; Dopamine; Dose; Elderly; Environmental Exposure; Environmental Risk Factor; Enzymes; Etiology; Exposure to; Foundations; Future; Glutathione; Goals; Homeostasis; Human; In Vitro; Incidence; Individual; Iron; Isoprostanes; Lead; Left; Link; Lipid Peroxidation; Lipids; Mammals; Manganese; Measures; Metabolism; Modeling; Movement Disorders; Muscle Rigidity; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Nutrient; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Patients; Pesticides; Prevention; Principal Investigator; Process; Rate; Rattus; Reactive Oxygen Species; Reporting; Research; Role; Sprague-Dawley Rats; Symptoms; Tissues; Toxic effect; Work; age group; age related; aged; antioxidant therapy; attenuation; base; brain cell; brain tissue; cell type; cofactor; cytotoxic; day; design; divalent metal; event cycle; in vivo; male; neurotoxicity; programs; research study; toxic metal

DESCRIPTION (provided by applicant): The overall goal of this project is to characterize the mechanism(s) in the brain involved in oxidative stress (e.g., lipid peroxidation) due to manganese (Mn) overexposure and the role(s) of glutathione in this process. Manganese is an essential nutrient for humans and other mammals, and it functions as a critical cofactor for many key enzymes involved in cellular metabolism. However, exceedingly high brain Mn concentrations are known to cause neurotoxicity (manganism) with symptoms similar to Parkinson's disease (PD). These similarities between Parkinson's disease and manganism include the presence of generalized bradykinesia and widespread rigidity. While the etiologies of both manganism and PD are not fully understood, recent evidence suggests that oxidative stress may be a factor in both disease processes. Glutathione (GSH) is a ubiquitous antioxidant that functions in conjugation and elimination of toxic molecules, thereby maintaining cellular redox homeostasis. GSH is one of the most important endogenous antioxidants in the brain with the astrocytes (cells that function as caretakers of neurons) being the cell with the richest supply of GSH. Alterations in GSH metabolism in the brain have been linked with oxidative stress and neurodegenerative diseases such as PD. Biochemical analyses of post-mortem brain tissues from PD patients and manganese exposed rats revealed significantly lowered GSH levels compared to controls. The objective of this project is to link alterations in GSH metabolism due to Mn exposure with lipid peroxidation, a known contributor to the neurodegenerative process. Our first Aim will use twenty-one day, three month, and twelve month old rats in order to assess in vivo GSH-redox status and the formation of isoprostanes a biomarker of lipid peroxidation in brain regions known to be vulnerable to Mn accumulation. Furthermore, some of the rats will be treated with antioxidants and we hypothesize that they will be spared from Mn-induced lipid peroxidation. Our second Aim is designed to specifically look at cellular mechanisms of these alterations in GSH metabolism due to Mn by utilizing both astrocyte and neuronal cell culture models. As in Aim one, we will expose both cell types to doses of Mn that are representative to those seen in cases of Mn neurotoxicity and assess the effects of antioxidant treatment on the formation of isoprostanes and alterations in GSH metabolism. Being that the astrocyte is the cell in the brain that handles the majority of GSH metabolism, it is likely that this model will reveal potential mechanisms in which manganese alters brain GSH and by performing parallel studies in neurons, we can assess the effects of Mn in these two brain cell types known to be targets of Mn accumulation. Together, both of these experimental approaches will build a foundation to hone future studies on mechanisms of neurodegenerative processes. PROJECT NARRATIVE: Idiopathic Parkinson's disease (IPD) represents a common neurodegenerative disorder affecting individuals aged 65 or older. Since this age group has increased 12% in the past decade and is projected to increase to 20% by the year 2030, it is likely that the incidence rate for IPD will dramatically increase. Environmental exposures to pesticides and toxic metals, including manganese (Mn), have been implicated in the development of IPD. Disturbances in brain glutathione (a natural antioxidant) metabolism have been reported in both Mn toxicity and in IPD. The overall goal of this study is to characterize the mechanism(s) in the brain involved in oxidative stress (e.g., lipid peroxidation) due to manganese (Mn) overexposure and the role(s) of glutathione in this process. If successful, these studies will lay the foundation for the development of a pharmacological therapy aimed at the prevention of neurodegenerative diseases that may be related to brain manganese accumulation.

描述(由申请人提供)：本项目的总体目标是描述由于锰(Mn)过量暴露而导致的大脑氧化应激(例如，脂质过氧化)的机制(S)以及谷胱甘肽在这一过程中的作用(S)。锰是人类和其他哺乳动物必需的营养物质，它是参与细胞代谢的许多关键酶的关键辅因子。然而，已知大脑中过高的锰浓度会导致神经毒性(锰中毒)，其症状类似于帕金森氏病(PD)。帕金森氏病和锰中毒之间的这些相似之处包括全身性运动迟缓和广泛的僵硬。虽然锰中毒和帕金森病的病因还不完全清楚，但最近的证据表明，氧化应激可能是这两种疾病过程中的一个因素。 谷胱甘肽(GSH)是一种普遍存在的抗氧化剂，其作用是结合和消除有毒分子，从而维持细胞氧化还原动态平衡。GSH是大脑中最重要的内源性抗氧化剂之一，星形胶质细胞(负责照看神经元的细胞)是GSH供应最丰富的细胞。大脑中GSH代谢的变化与氧化应激和帕金森病等神经退行性疾病有关。帕金森病患者和接触锰的大鼠死后脑组织的生化分析显示，与对照组相比，GSH水平显著降低。 该项目的目标是将锰暴露引起的GSH代谢变化与脂质过氧化联系起来，脂质过氧化是神经退化过程的已知贡献者。我们的第一个目标将使用21天、3个月和12个月龄的大鼠来评估体内GSH氧化还原状态和异前列腺素的形成，异前列腺素是大脑中已知易受锰积累影响的区域中脂质过氧化的生物标志物。此外，一些大鼠将接受抗氧化剂治疗，我们假设它们将免于锰诱导的脂质过氧化。我们的第二个目标是利用星形胶质细胞和神经细胞培养模型，专门研究锰引起GSH代谢变化的细胞机制。作为目标一，我们将使这两种类型的细胞暴露于具有代表性的锰神经毒性案例中的剂量，并评估抗氧化剂治疗对异前列腺素形成和GSH代谢变化的影响。由于星形胶质细胞是大脑中处理大部分GSH代谢的细胞，因此该模型很可能揭示锰改变大脑GSH的潜在机制，并通过对神经元进行平行研究，我们可以评估这两种已知为锰积累靶点的脑细胞中锰的影响。总之，这两种实验方法将为磨练未来对神经退化过程机制的研究奠定基础。项目简介：特发性帕金森氏病(IPD)是一种常见的神经退行性疾病，影响65岁或以上的人。由于这一年龄组在过去十年中增长了12%，预计到2030年将增加到20%，因此IPD的发病率很可能会大幅增加。环境暴露于杀虫剂和有毒金属，包括锰(Mn)，与IPD的发展有关。脑谷胱甘肽(一种天然抗氧化剂)代谢紊乱在锰中毒和IPD中都有报道。这项研究的总体目标是描述由于锰(Mn)过量暴露在大脑中参与氧化应激(例如，脂质过氧化)的机制(S)以及谷胱甘肽在这一过程中的作用(S)。如果成功，这些研究将为开发一种药物疗法奠定基础，该疗法旨在预防可能与脑内锰蓄积有关的神经退行性疾病。

项目成果

Manganese exposure inhibits the clearance of extracellular GABA and influences taurine homeostasis in the striatum of developing rats.

• DOI: 10.1016/j.neuro.2010.09.002
• 发表时间: 2010-12
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Fordahl SC;Anderson JG;Cooney PT;Weaver TL;Colyer CL;Erikson KM
• 通讯作者: Erikson KM

Waterborne manganese exposure alters plasma, brain, and liver metabolites accompanied by changes in stereotypic behaviors.

• DOI: 10.1016/j.ntt.2011.10.003
• 发表时间: 2012-01
• 期刊: NEUROTOXICOLOGY AND TERATOLOGY
• 影响因子: 2.9
• 作者: Fordahl, Steve;Cooney, Paula;Qiu, Yunping;Xie, Guoxiang;Jia, Wei;Erikson, Keith M.
• 通讯作者: Erikson, Keith M.