Susceptibility of Primate Dopamine Neurons to Toxicity During Development

描述(申请人提供)：甲基苯丙胺和MPTP都通过氧化应激机制对成年人类和成人以及非人类灵长类动物的多巴胺神经元产生毒性。在R21 NINDS赠款的支持下，最近的发现表明，婴儿和妊娠晚期的胎儿猴子对甲基苯丙胺和MPTP都有显著的抗药性，并提出了关于发育中的多巴胺神经元氧化应激机制的差异的问题。这项探索性拨款支持的其他研究已经确定了灵长类多巴胺神经元经历自然细胞凋亡死亡的时间段。在细胞自然死亡的高峰期，胎儿多巴胺神经元对甲基苯丙胺或MPTP的毒性作用非常敏感。总而言之，这些研究发现了怀孕期间的一个脆弱窗口，在这个窗口中，甲基苯丙胺或MPTP对未成熟的多巴胺神经元有毒性，可能是通过对氧化应激源的反应发生发育变化。拟议中的研究将通过调查发育期间和成年猴子对MPTP和甲基苯丙胺影响的差异敏感性的机制(S)来继续这些发现。我们将检测中脑多巴胺系统在不同发育阶段对MPTP和甲基苯丙胺的生化反应，看看氧化应激程度、解偶联蛋白-2活性、神经营养因子、黑质谷氨酸神经支配和/或DNA修复机制的差异是否解释了观察结果。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。除了作为氧化应激的模型，研究中使用的实际药物也具有临床意义。MPTP在结构上与与帕金森病有关的除草剂有关。甲基苯丙胺目前是一种被广泛滥用的药物，但此前还没有关于甲基苯丙胺对发育中的灵长类脑多巴胺神经元的毒性的研究。这项研究将加强我们对大脑发育中的多巴胺神经元对氧化应激不断变化的脆弱性的生化理解，并可能确定保护多巴胺神经元免受神经退化的策略。与公共健康相关：我们的数据显示，在灵长类动物发育的特定时期暴露于氧化应激会对大脑中的多巴胺神经元造成夸大的损害。给猴子注射甲基苯丙胺或MPTP药物是为了建立氧化应激模型。这些研究与患帕金森氏症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。

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.