DOPAMINERGIC NEUROTOXINS AND AGING

描述：（申请人摘要）帕金森病（PD），a 病因不明的神经退行性疾病， 我们的老年人，其特点是大量的中脑多巴胺能神经元的损失， (DA)神经元和去甲肾上腺素能（NA）和肾上腺素能（5 HT）的一些损失 核斑和中缝核中的神经元。 的目标 这项研究的目的是探讨潜在的神经保护作用， 单胺能神经元的突触囊泡。 前提是 单胺能神经元的各种群体内的突触囊泡可 为神经毒素提供了一个储存室，从而减少了 细胞质中能产生损伤的游离毒素。 1-甲基-4-苯基-1，2，3，6-四氢吡啶及其毒性代谢产物 将使用1-甲基-4-苯基吡啶鎓（MPP+），因为它们是有效的 因为MPP+是突触的一个很好的底物， 囊泡单胺转运体 有明显的差异， 大鼠和小鼠对MPTP诱导的DA神经元变性的易感性 这与神经元所处的MPP+的量无关。 暴露了 这些发现表明，可能有更大的 大鼠DA神经元内MPP+的细胞内隔离， 小鼠 神经毒性反应的这种种属差异将用于测试 假设。 在其他研究中，囊泡隔离在NA中的作用 和5 HT神经元和MPTP毒性将被评估。 一个多学科 将采用的方法，包括体内和体外研究， 神经化学和免疫组织化学研究。 具体目标是 项目是：1）以确定是否差异的能力囊泡 从大鼠或小鼠的新纹状体获得的MPP+的积累有助于 多巴胺能神经元的敏感性的物种差异， MPTP/MPP+诱导的神经毒性; 2）进一步检查体内MPTP/MPP+诱导的神经毒性。 MPTP给药引起的单胺能神经元变性 3）检查是否利血平化 动物影响MPP+在脑内积累的MPTP生物分布; 4)比较纹状体内神经元损伤的剂量反应曲线， MPP+在用或不用囊泡药物治疗的小鼠和大鼠中的输注 摄取抑制剂 囊泡可能提供储存 外源性或内源性神经毒素的位点是一种新的和有趣的 概念. 这反过来又提出了一个问题，即 单胺能神经元的囊泡功能可能有助于 在PD中观察到的神经变性。

DESCRIPTION: (Applicant's abstract) Parkinson's Disease (PD), a neurodegenerative disorder of unknown etiology which afflicts a large number of our elderly, is characterized by a massive loss of midbrain dopaminergic (DA) neurons and some loss of noradrenergic (NA) and serotonergic (5HT) neurons in the locus coreuleus and raphe nuclei, respectively. The goal of the proposed research is to investigate the potential neuroprotective role of synaptic vesicles in monoaminergic neurons. The hypothesis is that synaptic vesicles within various populations of monoaminergic neurons can provide a storage compartment for neurotoxins and thus reduce the amount of free toxin in the cytosol capable of producing damage. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its toxic metabolite 1-methyl-4-phenylpryidinium (MPP+) will be used because they are potent neurotoxins and because MPP+ is an excellent substrate for the synaptic vesicle monoamine transporter. There are marked differences in the susceptibility of rats and mice to MPTP-induced degeneration of DA neurons which is not associated with the amount of MPP+ to which the neurons are exposed. These findings suggest that there may be a much greater intracellular sequestration of MPP+ within DA neurons in rats as compared to mice. This species difference in neurotoxic response will be used to test the hypothesis. In other studies, the role of vesicular sequestration in NA and 5HT neurons and MPTP toxicity will be evaluated. A multidisciplinary approach will be utilized, including in vivo and in vitro studies, neurochemical and immunohistochemical studies. The specific aims of this project are: 1) to determine if differences in the capacity of vesicles obtained from the neostriata of rats or mice to accumulate MPP+ contribute to the species differences in the sensitivity of dopaminergic neurons to MPTP/MPP+-induced neurotoxicity; 2) to further examine in vivo the degeneration of monoaminergic neurons produced by the administration of MPTP to mice with dysfunctional vesicles; 3) to examine if reserpinization of animals affects MPTP biodistribution of MPP+ accumulation within the brain; 4) to compare dose-response curves for damage produced by intrastriatal infusions of MPP+ in mice and rats treated with or without a vesicular uptake inhibitor. The possibility that vesicles might provide a storage site for exogenous or endogenous neurotoxins is a novel and intriguing concept. This in turn raises the question as to whether defects in vesicular function of monoaminergic neurons might contribute to the neurodegeneration seen in PD.