NEURAL DEGENERATION INDUCED BY TETRAHYDROPYRIDINE ANALOG

四氢吡啶类似物诱导的神经变性

• 批准号: 3403281
• 负责人: RICHARD E. HEIKKILA
• 金额: $ 9.87万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1987-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3403281
• 关键词: Parkinson's disease; adrenergic agents; animal age group; chromatography; disease /disorder model; drug adverse effect; drug metabolism; genetic strain; neural degeneration; neurochemistry; neurologic manifestations; neurotoxins; neurotransmitters; nicotine; radioassay; sign /symptom; sympathetic nervous system; synaptosomes

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a commercially available compound that can be formed as a by-product in the synthesis of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). MPPP is a potent analgesic agent structurally similar to other widely used analgesic agents including meperidine and alphaprodine. It was recently reported that the inadvertent ingestion of small amounts of MPTP, mixed with varying amounts of MPPP and perhaps other agents, caused an irreversible Parkinsonism in several young individuals, who were most likely attempting to simulate the actions of heroin with MPPP. It has also been reported that the injections of MPTP alone to mondeys caused symptoms and pathology consistent with Parkinsonism, including a servere dopamine depletion and destruction of the substantia nigra. It thus appears likely that the agent responsible for the Parkinsonism observed in the young drug addicts was MPTP or a metabolite. The discovery that a simple substance of this nature administered systemically can reproduce so closely the pathology of Parkinson's disease has enormous implications for the etiology of the naturally occurring human disease. It suggests that a similar neurotoxin, exogenous or endogenous, may be involved in the pathogenesis of the disease. It has been reported by others that MPTP could not produce symptoms of Parkinson's disease in other species including rats and cats. However, we have discovered that MPTP administration to mice (two to ten daily injections) produces features of dopaminergic neuronal destruction, including large and long-lasting decrements in neostriatal levels of dopamine and its metabolites and in the capacity of neostriatal brain tissue to accumulate 3H-dopamine. In the present research project, we hope to expand on our findings and to develop the MPTP treated mouse as an animal model for Parkinson's disease. 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. Since all of these findings with MPTP are relatively recent and so little is known about MPTP, anything that we discover concerning the actions of MPTP can potentially be important. It is hoped that we will 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-1，2，5，6-四氢吡啶（MPTP）是一种商业上可接受的 可获得的化合物，其可以在合成 1-甲基-4-苯基-4-丙酰氧基-哌啶（MPPP）。 MPPP是一种有效的 结构上类似于其它广泛使用的镇痛剂的镇痛剂 包括哌替啶和阿法普定。 最近有报道称， 无意中摄入少量MPTP，混合不同数量的 MPPP和其他可能的药物，导致了不可逆的帕金森病， 几个年轻人，谁是最有可能试图模拟 海洛因与MPPP的作用。 另据报道， 单独注射MPTP给Mondeys引起的症状和病理 与帕金森症一致，包括严重的多巴胺耗竭， 破坏黑质。 因此，似乎代理人 在年轻吸毒者中观察到的帕金森症的原因是 MPTP或代谢物。 发现这种性质的简单物质 全身给药可以复制如此接近的病理 帕金森氏病的病因有巨大的影响， 自然发生的人类疾病。 它表明一种类似的神经毒素， 外源性或内源性的，可能参与的发病机制 疾病 据其他人报道，MPTP不能产生 帕金森病的症状在其他物种，包括老鼠和猫。 然而，我们已经发现，MPTP给药小鼠（2至10只）， 每日注射）产生多巴胺能神经元破坏的特征， 包括新纹状体内的 多巴胺及其代谢产物和新纹状体脑的能力 组织积聚3H-多巴胺。 在本研究项目中，我们希望 为了扩大我们的发现，并开发MPTP治疗的小鼠作为一种 帕金森病的动物模型。 第二个更重要的目标是 尽可能多地了解MPTP作用的基本特征 和许多类似的结构。 由于MPTP的所有这些发现 是相对较新的，所以很少有人知道MPTP，任何我们 发现有关MPTP的作用可能是重要的。 它 希望我们能够确定确切的作用方式， MPTP。 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和特发性帕金森病的病因， 人类