NEUROTOXINS AND ANIMAL MODELS OF NEUROLOGICAL DISEASES

该项目的目标是确定毒素的特性， 其靶向特定的神经系统，决定作用机制 这些毒素，并用它们来制造人类神经系统的动物模型， 紊乱目前主要关注的是两种毒素， 1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）和 β-甲基氨基丙氨酸（BMAA）。 MPTP通过颈内动脉给药， 猴子的偏侧帕金森症这些动物被用来评估变化 脑代谢（如通过放射自显影测定脑组织中的 14 C-2-脱氧葡萄糖的摄取）作为毒素诱导的神经系统损伤的结果。 并检查组织植入物在减轻 神经系统缺陷检查生化和行为异常 评估组织植入物替代受损神经元的功效， 增强存活神经元的发芽。在其他研究中， 与各种剂量的MPTP和可能增强其 毒性作用。从放置在MPTP中的明胶海绵和手术中获得的液体 检查受损大脑中刺激神经元生长的物质 在组织培养中。通过低剂量乙醇或 乙醛不是由于对MPTP代谢或保留的任何影响， 其代谢产物MPP+。这种毒性增强现在已被证明是 在幼龄（7日龄）小鼠中可忽略不计，但在老龄（8周龄）小鼠中显著 动物此外，乙醇或乙醛似乎增强了 毒素在靶向特定多巴胺能神经元方面的特异性。凝胶 从MPTP尾状核的空腔中取出泡沫塞 帕金森病猴含有促进神经突生长的可溶性物质 在组织培养的神经元中生长。类似的物质在 胎儿组织包括羊膜 BMAA被认为是导致面粉毒性的原因 从苏铁中产生，并被认为是一个致病因素， 关岛肌萎缩侧索硬化-帕金森综合征-痴呆综合征 （关岛ALS-PD）。来自关岛的面粉样本以及苏铁植物 从不同的来源已经分析（通过GC-MS）苏铁的加工 为了生产面粉，去除了大于80%的BMAA（通常超过 95%），并且残留的BMAA含量不足以达到甚至很小的 据报告对猴子有毒的数量的一部分。BMAA内容 来自不同来源的面粉的毒性进行了比较， 使用颗粒细胞组织培养物进行体外培养。在面粉中的浓度， BMAA对这些细胞没有毒性，但一些面粉样品有毒。 仅在有毒样品中发现高浓度的锌。镀锌 金属容器可能被用于制备这些样品， 面粉，暗示锌是与关岛ALS-PD有关的有毒金属。

The objectives of this project are to identify and characterize toxins which target specific neuronal systems,determine the mechanisms of action of these toxins, and use them to produce animal models of human neurologic disorders. At present the main focus is on two toxins, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and beta-methylaminoalanine (BMAA). MPTP is administered via the internal carotid artery to produce hemiparkinsonism in monkeys. These animals are used to evaluate changes cerebral metabolism (as indicated by autoradiographic determination of the uptake of 14C-2-deoxyglucose) as a result of the toxin-induced neurologic disorder and to examine the efficacy of tissue implants in alleviating the neurologic deficits. Biochemical and behavioral abnormalities are examined to evaluate the efficacy of tissue implants to replace destroyed neurons or enhance sprouting of surviving neurons. In other studies, mice are treated with various doses of MPTP and with substances which may potentiate its toxic effects. Fluid obtained from gelfoam placed in MPTP and surgically damaged brain is examined for substances which stimulate growth of neurons in tissue culture. Enhancement of MPTP toxicity by low doses of ethanol or acetaldehyde is not due to any effect on MPTP metabolism or retention of its metabolite, MPP+ .This enhancement of toxicity has now been shown to be negligible in young (7-day-old) mice, but marked in older (8-week-old) animals. Furthermore, ethanol or acetaldehyde appears to enhance the specificity of the toxin in targeting specific dopaminergic neurons. Gel foam plugs removed from cavities made in the caudate nucleus of MPTP parkinsonian monkeys contains soluble substance(s) which promotes neurite outgrowth in tissue cultured neurons. Similar substances have been found in fetal tissues, including amnion. BMAA has been implicated as responsible for the putative toxicity of flour produced from cycas circinalis and cited as one etiologic factor in the Amytrophic lateral sclerosis-parkinsonism-dementia complex of Guam (Guamanian ALS-PD). Samples of a flour from Guam as well as cycad plants from various sources have been assayed (by GC-MS) Processing of the cycad to produce the flour removes greater than 80% of the BMAA (usually over 95%) and the residual BMAA content is not sufficient to reach even a small fraction of the amounts reported to be toxic in monkeys. The BMAA contents of flour from various sources have been compared with toxicity elicited in vitro using granule cell tissue cultures. At the concentrations in flour, BMAA is not toxic to these cells but some of the flour samples were toxic. High concentrations of zinc were found in only toxic samples. Galvanized metal containers might have been used in preparation of these samples of flour, implicating zinc as a toxic metal related to Guamanian ALS-PD.