NEURAL DEGENERATION BY TETRAHYDROPYRIDINE ANALOGS

四氢吡啶类似物引起的神经变性

• 批准号: 3403280
• 负责人: RICHARD E. HEIKKILA
• 金额: $ 11.9万
• 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 1994-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3403280
• 关键词: Parkinson's disease; adrenergic agents; animal age group; chromatography; disease /disorder model; drug adverse effect; drug metabolism; genetic strain; laboratory mouse; laboratory rat; model design /development; neural degeneration; neurochemistry; neurotoxins; neurotransmitters; nicotine; radioassay; sympathetic nervous system; synaptosomes

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be formed as a by-product in the synthesis of l-methyl-4-phenyl-4- propionoxypiperidine (MPPP), a potent analgesic agent structurally similar to other widely used analgesics including meperidine. It is 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 n animal model of parkinsonism. A second and more important goal is to learn as much s 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 an 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 here are similarities in the etiology of parkinsonism caused in experimental animals by MPTP and the etiology of idiopathic parkinsonism in humans.

可生成1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP） 作为合成1-甲基-4-苯基-4-甲基苯甲酰胺的副产物， 丙氧哌啶（MPPP），一种有效的镇痛剂，结构 类似于其他广泛使用的镇痛药，包括哌替啶。 它 据报道，几年前，摄入MPTP，混合 不同数量的MPPP和其他可能的代理人，造成了 在几个年轻的成年人，谁是最不可逆转的帕金森症 可能是想用MPPP模拟海洛因的行为 它 也有报道称，单独给猴子注射MPTP 导致了帕金森综合征的症状和病理 它 由此看来帕金森症的病因 是MPTP或其代谢物。 的 发现全身给予的简单物质可以 如此接近地再现了帕金森病的病理学 对人类帕金森症的病因学有着巨大的影响。 它 表明类似的神经毒素，外源性或内源性， 参与疾病的发病机制。 此前有 报告称MPTP给药不会产生帕金森病 包括老鼠在内的其他物种的症状。 但我们 发现给小鼠施用MPTP产生了 多巴胺能神经元破坏，包括神经细胞损失 在黑质的腹侧，大而长， 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 活动 在本研究中，我们希望进一步发展 MPTP处理的小鼠作为帕金森综合征的动物模型。 第二和 更重要的目标是尽可能多地了解基本的 MPTP及其许多结构类似物的作用特征。 我们最近发现几种MPTP类似物具有神经毒性， 比MPTP本身更重要。 所有这些发现与MPTP及其 类似物是相对较新的，我们发现的任何东西 关于MPTP或其类似物的作用， 重要. 我们希望能够确定 MPTP的作用。 整个项目的总体目标是 以确定是否有相似的病因， MPTP引起的实验动物帕金森综合征， 人类特发性帕金森综合征的病因学