NEURAL DEGENERATION INDUCED BY TETRAHYDROPYRIDINE ANALOGS

四氢吡啶类似物引起的神经变性

• 批准号: 3882329
• 负责人: RICHARD E HEIKKILA
• 金额: --
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3882329
• 关键词: 6 hydroxydopamine; MAO inhibitors; Parkinson's disease; animal age group; basal ganglia; behavior disorders; chemical structure function; disease /disorder model; dopamine; dopamine receptor; drug metabolism; enzyme mechanism; genetic strain; laboratory mouse; laboratory rat; manganese; methamphetamine; model design /development; neural degeneration; neurons; neurotoxins; sex; toxicology

1-Methy1-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be formed as a by-product in the synthesis of 1-methy1-4-phenyl-4- propionoxypiperidine (MPPP), a potent analgesic agent structurally similar to other widely use analgesics including meperidine. It was reported a few years ago that the ingestion of MPTP, mixed with varying amounts of MPPP and perhaps other agents, caused an irreversible parkinsonism in several young adults who were most likely attempting to simulate the actions of heroin with MPPP. It was also reported that the injection of MPTP alone to monkeys caused symptoms and pathology consistent with parkinsonism. It thus appears that the agent responsible for the parkinsonism observed in the young drug abusers was MPTP or a metabolite. The discovery that a simple substance administered systemically can reproduce so closely the pathology of Parkinson's disease has enormous implications for the etiology of human parkinsonism. It suggests that a similar neurotoxin, exogenous or endogenous, may be involved in the pathogenesis of the disease. It was previously reported that MPTP administration did not produce parkinsonian symptoms in certain other species including rats. However, we discovered that MPTP administration to mice produced features of dopaminergic neuronal destruction, including a loss of nerve cells in the zona compacta of the substantia nigra and large and long-lasting decrements: 1) in neostriatal levels of dopamine and its metabolites, 2) in the capacity of neostriatal brain tissue to accumulate 3H-dopamine, and 3) in neostriatal tyrosine hydroxylase activity. In the present study we hope to further develop the MPTP-treated mouse as an animal model of parkinsonism. A second and more important goal is to learn as much as possible about the basic features of the action of MPTP and many of its structural analogs. We have recently found several MPTP analogs to be neurotoxic, some more so than MPTP itself. All of these findings with MPTP and its analogs are relatively recent, and anything that we discover concerning the actions of MPTP or its analogs can potentially be important. We hope to be able to determine the exact mode of action of MPTP. An overall goal underlying this entire project is to determine if there are similarities in the etiology of parkinsonism caused in experimental animals by MPTP and the etiology of idiopathic parkinsonism in humans.

1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）可以是 在合成1-甲基-4-苯基-4-甲基-1H-吡唑的过程中作为副产物形成。 丙氧哌啶（MPPP），一种强效镇痛剂 在结构上类似于其它广泛使用镇痛剂 哌替啶 几年前有报道称， MPTP，与不同量的MPPP混合，也许还有其他 在几个年轻人中引起了不可逆转的帕金森症 成年人最有可能试图模仿 海洛因和MPPP 另据报道， MPTP单独给猴引起的症状和病理 符合帕金森综合征 由此看来， 在年轻的药物中观察到的帕金森症的原因 是MPTP或代谢物。 发现一个简单的 全身给予的物质可以如此紧密地复制， 帕金森病的病理学对 人类帕金森综合征的病因学 这表明，类似的 神经毒素，外源性或内源性，可能涉及在 疾病的发病机制。 之前有消息称 MPTP给药未引起帕金森病症状， 包括老鼠在内的其他物种。 然而，我们发现， MPTP给药小鼠产生多巴胺能神经元的特征， 神经元的破坏，包括神经细胞的损失， 黑质神经节，大而持久 递减：1）在新纹状体多巴胺水平及其 代谢物，2）在新纹状体脑组织的能力， 积累3 H-多巴胺，和3）在新纹状体酪氨酸 羟化酶活性 在本研究中，我们希望进一步 将MPTP处理的小鼠开发为以下动物模型： 帕金森综合征 第二个更重要的目标是学习， 尽可能多地了解MPTP作用的基本特征 和许多类似的结构。 我们最近发现 几种MPTP类似物具有神经毒性，有些比MPTP更强 本身 MPTP及其类似物的所有这些发现都是 相对较新的，我们发现的任何关于 MPTP或其类似物的作用可能是重要的。 我们 希望能够确定MPTP的确切作用方式。 整个项目的总体目标是确定 帕金森症的病因有相似之处， 实验动物MPTP和特发性 人类帕金森病。