NEURAL DEGENERATION INDUCED BY TETRAHYDROPYRIDINE ANALOG

四氢吡啶类似物诱导的神经变性

• 批准号: 3403279
• 负责人: RICHARD E. HEIKKILA
• 金额: $ 9.3万
• 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/3403279
• 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) 是一种商业化产品 可以作为合成中的副产物形成的可用化合物 1-甲基-4-苯基-4-丙氧基-哌啶（MPPP）。 MPPP 是一种有效的 结构与其他广泛使用的镇痛剂相似的镇痛剂 包括哌替啶和阿法普罗定。 近日有报道称， 无意中摄入少量与不同量混合的 MPTP MPPP 和其他药物可能导致不可逆转的帕金森病 几个年轻人，他们很可能试图模拟 海洛因与 MPPP 的行为。 另据报道， 单独向蒙迪斯注射 MPTP 引起症状和病理 与帕金森症一致，包括严重的多巴胺耗竭和 黑质的破坏。 因此，代理人很可能 造成年轻吸毒者出现帕金森病的原因是 MPTP 或代谢物。 发现这种性质的单质 系统地施用可以如此接近地再现病理学 帕金森病对其病因学具有巨大影响 自然发生的人类疾病。 这表明类似的神经毒素， 外源性或内源性，可能参与该病的发病机制。 疾病。 据其他人报道 MPTP 无法产生 其他物种（包括老鼠和猫）的帕金森病症状。 然而，我们发现对小鼠（2 至 10 只）进行 MPTP 给药 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且长期的下降 多巴胺及其代谢物与新纹状体脑的能力 组织积累3H-多巴胺。 在目前的研究项目中，我们希望 扩展我们的发现并将 MPTP 处理的小鼠开发为 帕金森病动物模型。 第二个也是更重要的目标是 尽可能多地了解MPTP动作的基本特征 及其许多结构类似物。 由于 MPTP 的所有这些发现 相对较新，人们对 MPTP 知之甚少，我们知道的任何事情 发现 MPTP 的行为可能很重要。 它 希望我们能够确定确切的行动方式 多点传输协议。 整个项目的总体目标是确定是否 帕金森病的病因学有相似之处 MPTP实验动物及特发性帕金森病的病因学 人类。