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Mechanism and Treatment of Manganese Toxicity

锰中毒的机制及治疗

基本信息

批准号：
7729078
负责人：
JEROME Allan ROTH
金额：
$ 23.54万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729078
关键词：
Amyotrophic Lateral Sclerosis Animal Model Antioxidants Apoptotic Behavioral Biochemical Biochemical Process Brain Calcium Cell Death Cells Chromatin Chronic Cultured Cells DNA Fragmentation DNA Nucleotidylexotransferase Disease Dose Effectiveness Embryo Excitatory Amino Acid Antagonists Fibrinogen Functional disorder Generations Globus Pallidus Glutamate Receptor Glutamates Goals Grant Health Hepatic Human Immunofluorescence Immunologic Individual Injection of therapeutic agent Intoxication JNK-activating protein kinase Label Lead Lesion Liver Cirrhosis MAPK11 gene MAPK14 gene MAPK8 gene Malignant Epithelial Cell Manganese Marketing Measures Mediating Membrane Potentials Metabolism Mitochondria Mus N-Methylaspartate NMDA receptor antagonist Neurologic Neuronal Injury Neurons Neurotoxins Neurotransmitters Nuclear Structure Occupational Exposure Overdose Oxidative Stress Oxygen Parkinson Disease Pharmaceutical Preparations Phosphotransferases Physical condensation Play Predisposition Printing Procedures Process Riluzole Role Signal Transduction Staging Staining method Stains Structure of subthalamic nucleus Substantia nigra structure Suggestion Symptoms Synapses Syndrome Testing Time Toxic Actions Toxic effect base caspase-3 computerized data processing cresyl violet cytotoxic deoxyuridine triphosphate design dopaminergic neuron effective therapy inhibitor/antagonist mitochondrial dysfunction neurotoxic prevent public health relevance response uptake

项目摘要

DESCRIPTION (provided by applicant): Manganese (Mn) intoxication, a syndrome known as manganism, is most often associated with prolonged occupational exposure, although individuals with cirrhosis of the liver and related hepatic dysfunction display many of the behavioral and neurological symptoms associated with this disorder. The most prominent symptom from overexposure comprises an irreversible extrapyramidal dysfunction resembling that of Parkinson's disease. Manganism, however, is associated with the preferential degeneration of GABAminergic neurons within the globus pallidus and not the dopaminergic neurons in the substantia nigra. Although the neurotoxic mechanisms provoking increased susceptibility of pallidal neurons to the toxic actions of Mn is not fully understood, there is increasing evidence that the excitatory neurotransmitter, glutamate, as playing a role in the degenerative actions of Mn since neurons within the globus pallidus normally receive glutaminergic input from cells within the subthalamic nuclei. This is supported by studies demonstrating that blocking of the glutamate receptors with the NMDA receptor antagonist, MK-801, prevents lesions produced by intrastriatal injections of Mn. This raises the issue that the selective neurotoxic actions of Mn on pallidal neurons may not be caused by any one factor but are likely an amalgamation of several processes occurring simultaneously which include 1) accumulation of Mn in the globus pallidus, 2) similarity between the cytotoxic actions of glutamate and Mn involving mitochondrial dysfunction leading to oxidative stress, 3) Mn inhibition of astrocytic glutamate transport and metabolism leading to increase synaptic levels of glutamate and 4) increased uptake of Mn in pallidal neurons by activated glutamate channels. Thus, it is reasonable to hypothesize that treatment of Mn overdoses with a drug which inhibits both glutamate release and oxidative stress may prove useful in the initial stages of manganism. Interestingly, there is a drug on the market, riluzole, currently approved for treatment of amyotrophic lateral sclerosis (ALS), which mechanistically behaves in this fashion. Riluzole functions by inhibiting glutamate release as well as its actions as both an antioxidant and an antagonist of the ionotropic glutamate receptor. Thus, the combined pharmacological actions of riluzole as both an antioxidant and inhibitor of glutamate activity may make it an ideal drug for the treatment of manganism. As will be described in more detail in this proposal, our preliminary studies, in fact, support this hypothesis. Accordingly, the studies proposed in this grant are designed to 1) examine the mechanism by which glutamate facilitates Mn toxicity, 2) characterize the biochemical mechanisms responsible for the neuroprotective actions of riluzole and 3) demonstrate the neuroprotective actions of riluzole in Mn exposed mice. PUBLIC HEALTH RELEVANCE Overexposure to high atmospheric levels of manganese can lead to a syndrome characterized by an irreversible extrapyramidal dysfunction resembling that of Parkinson's disease. Although it is known that manganism is associated with the preferential degeneration of GABAminergic neurons, the mechanism for this selective toxicity is not fully understood. Thus, the studies proposed in this grant is relevant to human health in that it will investigate new mechanisms to explain the selective toxic actions of manganese in human brain and provide the necessary preliminary evidence to demonstrate the application of the drug, riluzole, for treatment of this debilitating and irreversible disorder.

描述（由申请人提供）：锰（Mn）中毒是一种被称为锰中毒的综合征，最常与长期职业暴露相关，尽管肝硬化和相关肝功能障碍患者表现出许多与这种疾病相关的行为和神经症状。过度活动最突出的症状包括不可逆的锥体外系功能障碍，类似于帕金森病。然而，锰中毒与苍白球内GABA能神经元的优先变性有关，而与黑质中多巴胺能神经元的优先变性无关。虽然引起苍白球神经元对Mn毒性作用的敏感性增加的神经毒性机制尚未完全了解，但越来越多的证据表明兴奋性神经递质谷氨酸在Mn的退行性作用中起作用，因为苍白球内的神经元通常从丘脑底核内的细胞接收多巴胺能输入。这得到了研究的支持，研究表明，用NMDA受体拮抗剂MK-801阻断谷氨酸受体可预防纹状体内注射Mn产生的病变。这提出了Mn对苍白球神经元的选择性神经毒性作用可能不是由任何一个因素引起的，而是可能是同时发生的几个过程的合并，包括1）Mn在苍白球中的积累，2）谷氨酸和Mn的细胞毒性作用之间的相似性，涉及导致氧化应激的线粒体功能障碍，3）Mn抑制星形胶质细胞谷氨酸转运和代谢，导致谷氨酸的突触水平增加和4）通过激活的谷氨酸通道增加苍白球神经元中Mn的摄取。因此，这是合理的假设，治疗锰过量的药物，抑制谷氨酸释放和氧化应激可能证明是有用的锰中毒的初始阶段。有趣的是，市场上有一种药物，利鲁唑，目前被批准用于治疗肌萎缩侧索硬化症（ALS），其机制是以这种方式表现。阿曲唑通过抑制谷氨酸释放以及其作为抗氧化剂和离子型谷氨酸受体拮抗剂的作用发挥作用。因此，利鲁唑作为抗氧化剂和谷氨酸活性抑制剂的联合药理作用可能使其成为治疗锰中毒的理想药物。正如本提案中将更详细描述的那样，我们的初步研究事实上支持这一假设。因此，本授权中拟定的研究旨在1）检查谷氨酸促进Mn毒性的机制，2）表征负责利鲁唑神经保护作用的生化机制，3）证明利鲁唑在Mn暴露小鼠中的神经保护作用。与公众健康的关系过量摄入大气中高浓度的锰可导致一种综合征，其特征是类似帕金森氏病的不可逆的锥体外系功能障碍。虽然已知锰中毒与GABA能神经元的优先变性有关，但这种选择性毒性的机制尚未完全了解。因此，这项研究计划与人类健康有关，因为它将研究新的机制来解释锰在人脑中的选择性毒性作用，并提供必要的初步证据来证明药物利鲁唑用于治疗这种使人衰弱和不可逆的疾病。