NEURAL DEGENERATION INDUCED BY TETRAHYDROPYRIDINE ANALOG

四氢吡啶类似物诱导的神经变性

• 批准号: 3403282
• 负责人: RICHARD E. HEIKKILA
• 金额: $ 10.3万
• 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/3403282
• 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)是一种商品 可利用的化合物，可在合成过程中作为副产品形成 1-甲基-4-苯基-4-丙酰氧基哌啶(MPPP)MPPP是一种强有力的 止痛剂在结构上与其他广泛使用的止痛药相似 包括度冷丁和安非他定。最近有报道称， 不慎摄入少量MPTP，混合不同数量的MPTP MPPP和其他药物，导致了不可逆转的帕金森氏症 几个年轻人，他们很可能试图模拟 海洛因在MPPP中的行为。另有报道称， 单独向Mondeys注射MPTP引起症状和病理 符合帕金森氏症，包括严重的多巴胺缺乏和 黑质破坏。因此，看起来特工很可能 在年轻吸毒者身上观察到的帕金森氏症的责任是 MPTP或代谢物。发现这种性质的简单物质 全身给药可以如此紧密地复制 帕金森氏病对本病的病因有巨大的影响。 自然发生的人类疾病。这表明一种类似的神经毒素， 外源性或内源性，可能参与了本病的发病机制。 疾病。据其他人报道，MPTP无法产生 帕金森氏症在其他物种中的症状，包括老鼠和猫。 然而，我们发现MPTP对小鼠(两到十个)的作用 每日注射)产生多巴胺能神经元破坏的特征， 包括新纹状体水平的大幅和长期下降 多巴胺及其代谢物与新纹状体脑容量 组织中蓄积~3H-多巴胺。在目前的研究项目中，我们希望 对我们的发现进行扩展并将MPTP处理的小鼠作为 帕金森氏病的动物模型。第二个也是更重要的目标是 尽可能多地了解MPTP的作用的基本特征 以及它的许多结构类似物。由于MPTP的所有这些发现 是相对较新的，因此对MPTP知之甚少，任何我们 发现MPTP的作用可能是很重要的。它 希望我们能够确定行动的确切模式 MPTP。整个项目的总体目标是确定 导致帕金森氏症的病因有相似之处 MPTP实验动物与特发性帕金森病的病因学研究 人类。