Susceptibility of Primate Dopamine Neurons to Toxicity During Development

灵长类多巴胺神经元在发育过程中对毒性的敏感性

• 批准号: 7774998
• 负责人: JOHN D ELSWORTH
• 金额: $ 35.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774998
• 关键词: Accounting; Address; Adult; American; Apoptotic; Behavioral; Biochemical; Blood; Brain; Cell Death; Central Nervous System Diseases; Cercopithecidae; Cognitive; DNA Repair; Data; Development; Dopamine; Drug usage; Embryo; Employee Strikes; Enzymes; Etiology; Exhibits; Exposure to; Fetus; Functional disorder; Glutamates; Grant; Herbicides; Human; Hypoxia; Infant; Infection; Inflammation; Measurement; Measures; Mental disorders; Methamphetamine; Midbrain structure; Modeling; Monkeys; Motor; National Institute of Drug Abuse; National Institute of Neurological Disorders and Stroke; Neonatal; Nerve Degeneration; Neurologic; Neurotoxins; Oxidative Stress; Parkinson Disease; Performance; Pharmaceutical Preparations; Predisposition; Pregnancy; Primates; Recovery; Research; Resistance; Risk; Rodent; Staging; Substantia nigra structure; System; Testing; Third Pregnancy Trimester; Time; Toxic effect; Toxin; Traumatic Brain Injury; UCP2 protein; Ubiquinone; Work; base; clinically relevant; dopamine system; dopaminergic neuron; drug of abuse; environmental agent; fetal; mature animal; neonate; nerve supply; neurogenesis; neurotoxic; neurotrophic factor; nonhuman primate; offspring; partial recovery; pregnant; prenatal; prenatal exposure; prevent; primate development; public health relevance; response; stem; stressor; young adult

DESCRIPTION (provided by applicant): Both methamphetamine and MPTP are toxic to dopamine neurons in the adult human and adult, non-human primate through mechanisms involving oxidative stress. Recent findings, supported by a R21 NINDS grant, have demonstrated a remarkable resistance to both methamphetamine and MPTP in the infant and late- gestational fetal monkey and raised questions concerning differences in the mechanisms of oxidative stress in developing dopamine neurons. Other studies supported by this exploratory grant have identified a time period that primate dopamine neurons undergo apoptotic natural cell death. During the peak of natural cell death, fetal dopamine neurons were sensitive to the toxic effects of methamphetamine or MPTP. Together these studies identify a vulnerable window in gestation where methamphetamine or MPTP are toxic to the immature dopamine neurons, potentially through developmental changes in the response to oxidative stressors. The proposed studies will pursue these findings by investigating the mechanism(s) of the differential sensitivity to the effects of MPTP and methamphetamine during development and in adult monkeys. We will examine the biochemical response of the midbrain dopamine system to MPTP and methamphetamine at various stages of development, to see whether differences in degree of oxidative stress, uncoupling protein-2 activity, neurotrophic factors, and glutamate innervation of the substantia nigra and/or DNA repair mechanisms explain the observations. This work has relevance to the etiology and treatment of neurological and psychiatric disorders that may be initiated by damage to developing dopamine neurons. Besides being models of oxidative stress, the actual drugs used in the studies also have clinical relevance. MPTP is structurally related to herbicides that have been implicated in Parkinson's disease. Methamphetamine is currently a widely abused drug, yet there have been no previous studies on the toxicity of methamphetamine on developing primate brain dopamine neurons. This research will enhance our biochemical understanding of the changing vulnerability of the developing brain dopamine neurons to oxidative stress, and may identify strategies for protecting dopamine neurons from neurodegeneration. PUBLIC HEALTH RELEVANCE: Our data shows that exposure to oxidative stress at a certain period in primate development induces exaggerated damage to dopamine neurons in the brain. The drugs methamphetamine or MPTP are administered to produce an oxidative stress model in the monkey. The studies have direct relevance to the risk of acquiring Parkinson's disease and to the behavioral consequences of exposure to drugs of abuse during development.

描述（由申请方提供）：甲基苯丙胺和MPTP均通过涉及氧化应激的机制对成年人和成年非人灵长类动物的多巴胺神经元具有毒性。最近的研究结果得到了R21 NINDS基金的支持，已经证明了婴儿和妊娠晚期胎猴对甲基苯丙胺和MPTP的显著抗性，并提出了关于发育中的多巴胺神经元中氧化应激机制差异的问题。这项探索性资助支持的其他研究已经确定了灵长类多巴胺神经元经历凋亡性自然细胞死亡的时间段。在细胞自然死亡高峰期，胎儿多巴胺神经元对甲基苯丙胺或MPTP的毒性作用敏感。这些研究共同确定了妊娠期的一个脆弱窗口，其中甲基苯丙胺或MPTP对未成熟的多巴胺神经元有毒，可能是通过对氧化应激反应的发育变化。拟议的研究将通过调查发育期间和成年猴对MPTP和甲基苯丙胺影响的不同敏感性的机制来追求这些发现。我们将研究中脑多巴胺系统的生化反应MPTP和甲基苯丙胺在不同的发展阶段，看看是否在氧化应激程度的差异，解偶联蛋白-2活性，神经营养因子，和谷氨酸神经支配的黑质和/或DNA修复机制解释的意见。这项工作与神经和精神疾病的病因学和治疗有关，这些疾病可能是由发育中的多巴胺神经元受损引起的。除了作为氧化应激模型外，研究中使用的实际药物也具有临床相关性。MPTP在结构上与帕金森病中涉及的除草剂有关。甲基苯丙胺是目前广泛滥用的药物，但以前没有关于甲基苯丙胺对发育中的灵长类大脑多巴胺神经元的毒性的研究。这项研究将增强我们对发育中的大脑多巴胺神经元对氧化应激的脆弱性变化的生物化学理解，并可能确定保护多巴胺神经元免受神经变性的策略。 公共卫生关系：我们的数据表明，在灵长类动物发育的某个时期暴露于氧化应激会导致大脑中多巴胺神经元的过度损伤。施用药物甲基苯丙胺或MPTP以在猴子中产生氧化应激模型。这些研究与获得帕金森病的风险以及在发育过程中暴露于滥用药物的行为后果直接相关。