NEURAL DEGENERATION INDUCED BY TETRAHYDROPYRIDINE ANALOGS

四氢吡啶类似物引起的神经变性

• 批准号: 3846785
• 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/3846785
• 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) 在合成1-甲基-4-苯基-4-丙酮的过程中形成的副产物 强效止痛药丙氧哌啶(MPPP) 在结构上类似于其他广泛使用的止痛药，包括 度冷丁。几年前有报道称，摄取 MPTP，与不同数量的MPPP混合，或许还有其他 在几个年轻人身上引起了不可逆转的帕金森氏症 成年人最有可能试图模拟 带有MPPP的海洛因。另有报道称，注射 MPTP单独对猴子引起的症状和病理 符合帕金森氏症。由此可见，该特工 对年轻药物中观察到的帕金森症负责 滥用者是MPTP或代谢物。发现一个简单的 系统给药的物质可以如此紧密地复制 帕金森氏病的病理学对 人类帕金森氏症的病因学。这表明，类似的 神经毒素，外源性或内源性，可能参与了 疾病的发病机制。此前有报道称， MPTP给药后未出现帕金森症状 包括老鼠在内的某些其他物种。然而，我们发现， MPTP给药小鼠产生多巴胺能特征 神经元破坏，包括小带内神经细胞的丢失 黑质致密带，大而持久 减少：1)新纹状体多巴胺及其受体水平 代谢产物，2)新纹状体脑组织的能力 蓄积~3H-多巴胺；3)新纹状体酪氨酸 羟基酶活性。在目前的研究中，我们希望进一步 建立MPTP处理小鼠的动物模型 帕金森症。第二个也是更重要的目标是学习 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。我们最近发现 几种MPTP类似物具有神经毒性，有些比MPTP更具毒性 它本身。所有这些关于MPTP及其类似物的发现都是 相对较新，以及我们发现的任何关于 MPTP或其类似物的行动可能很重要。我们 希望能够确定MPTP的确切作用模式。 整个项目的总体目标是确定 帕金森氏症的病因学有相似之处 MPTP实验动物与特发性疾病的病因学研究 人类患上帕金森氏症。