DOPAMINERGIC NEUROTOXINS AND AGING

描述：(申请人摘要)帕金森氏病(PD)， 病因不明的神经退行性疾病，困扰着大量患者 我们的老年人的特点是中脑多巴胺能大量丧失 (DA)神经元和部分去甲肾上腺素(NA)和5-羟色胺(5-HT)能神经元的丢失 核团和中缝核团中的神经元。的目标是 建议的研究是为了调查潜在的神经保护作用。 单胺能神经元中突触小泡的数量。假设是这样的 不同群体的单胺能神经元中的突触小泡可以 为神经毒素提供储藏室，从而减少 胞浆中的游离毒素能够产生损害。 1-甲基-4-苯基-1，2，3，6-四氢吡啶及其毒性代谢物 将使用1-甲基-4-苯基吡啶(MPP+)，因为它们是有效的 神经毒素，因为MPP+是突触的极好底物 囊泡单胺转运体。在这些方面有显著的不同 大鼠和小鼠对MPTP诱导的多巴胺能神经元变性的敏感性 这与神经元结合的MPP+的量无关 暴露了。这些发现表明，可能有更大的 大鼠多巴胺能神经元内MPP+的细胞内隔离 老鼠。这种神经毒性反应的物种差异将被用来测试 假设。在其他研究中，囊泡隔离在NA中的作用 并将评估5-羟色胺神经元和MPTP的毒性。一个多学科的 将利用包括体内和体外研究在内的方法， 神经化学和免疫组织化学研究。这样做的具体目的是 项目有：1)确定囊泡容量的差异 从大鼠或小鼠的新纹状体中获得MPP+的蓄积贡献 多巴胺能神经元对神经递质敏感性的物种差异 MPTP/MPP+诱导的神经毒性；2)进一步在体内检测 MPTP引起的单胺能神经元变性 对有功能障碍的囊泡的小鼠；3)检查利血平是否 动物影响MPTP在脑内积累MPP+的生物分布； 4)比较纹状体内损伤的剂量-反应曲线 小鼠和大鼠静脉输注MPP+前后的比较 摄取抑制剂。小泡可能提供储存的可能性 外源性或内源性神经毒素的位置是一个新颖而耐人寻味的地方 概念。这进而引发了这样一个问题，即是否存在缺陷 单胺能神经元的囊泡功能可能参与了 帕金森病患者出现神经变性。

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.