NEURAL DEGENERATION BY TETRAHYDROPYRIDINE ANALOGS

1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的合成 L-甲基-4-苯基-4-酮合成的副产物 丙氧基哌啶(MPPP)--结构上的强效止痛药 类似于其他广泛使用的止痛药，包括度冷丁。它 据报道，几年前摄取的MPTP，与 不同数量的MPPP，可能还有其他制剂，导致了 几个年轻人患有不可逆转的帕金森氏症，他们是最 很可能是试图用MPPP模拟海洛因的行为。它 也有报道称，单独向猴子注射MPTP 引起的症状和病理与帕金森氏症一致。它 因此，帕金森氏症的罪魁祸首 在年轻吸毒者身上观察到MPTP或代谢物。这个 一种通过全身给药的简单物质可以 帕金森氏病的病理学复制得如此之近 对人类帕金森症病因学的巨大影响。它 表明一种类似的神经毒素，无论是外源性还是内源性，可能 参与了这种疾病的发病机制。以前是这样的 报道称，MPTP管理部门没有产生帕金森氏症 包括老鼠在内的某些其他物种的症状。然而，我们 发现给小鼠注射MPTP会产生以下特征 多巴胺能神经元破坏，包括神经细胞丢失 在黑质致密带和大而长的- 持久的减少：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 3)在新纹状体酪氨酸羟化酶中积累~3H-多巴胺 活动。在目前的研究中，我们希望进一步发展 MPTP处理小鼠作为帕金森病动物模型。一秒钟，然后 更重要的目标是尽可能多地了解S的基本情况 MPTP及其许多结构类似物的作用特点。 我们最近发现了几个MPTP类似物具有神经毒性，有些 这比MPTP本身更重要。所有这些关于MPTP和ITS的发现 类比是相对较新的，我们发现的任何 关于MPTP或其类似物的作用，可能是 很重要。我们希望能够确定确切的模式 MPTP的动作。整个项目的总体目标是 以确定在病因上是否有相似之处 MPTP致实验动物帕金森病的实验研究 人类特发性帕金森综合征的病因学。

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.