MPTP TOXICITY AND ANIMAL MODELS OF PARKINSON'S DISEASE

1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）是一种神经毒素， 选择性破坏黑质纹状体多巴胺能神经元 途径，但在需要更高剂量的小鼠中特异性较低， 也影响到其他领域。 一个偏侧帕金森模型已经被开发出来， 通过将MPTP注入猴子的颈内动脉。 的 行为效应（转向病变侧）提供了 一种用于激动剂（其逆转了 和程序的影响，以刺激再生或取代 通过植入产生多巴胺的细胞 的参与 多巴胺能神经元和受体特性的变化， 神经元损伤正在使用生物化学技术进行检查， 多巴胺、去甲肾上腺素和血清素的测量及其 代谢物以及放射性标记配体与受体的结合， 酪氨酸羟化酶的荧光。 这些都证实了单方面 尾壳核多巴胺神经支配的破坏 偏侧帕金森病猴和增加D2受体在这方面， 动物 正计划使用18F-DOPA进行PET扫描， MPTP处理后猴脑的变性-再生过程。 其毒性机制与代谢产物吡啶衍生物有关 (MPP+），其在多巴胺能神经元中积累。 MPP+的毒性可能 涉及自由基和对神经黑色素的亲和力。 在小鼠中， 增强（例如，铜螯合剂）或减轻（例如，还原剂） MPTP毒性提供了参与超氧自由基的证据 对胺积累神经元造成毒性损伤。

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin which causes selective destruction of dopaminergic neurones of the nigro-striatal pathway in monkeys, but is less specific in mice requiring higher doses and affecting other areas as well. A hemiparkinsonian model has been developed by infusion of MPTP into the internal carotid artery of monkeys. The behavioral effects (turning in the direction of the lesioned side) provide a useful means for functional evaluation of agonists (which reverse the turning) and of effects of procedures to stimulate regeneration or replace by implantation dopamine-producing cells. The involvement of the dopaminergic neurones and changes in receptor properties as a result of neuronal damage are being examined using biochemical techniques for measurement of dopamine, norepinephrine, and serotonin and their metabolites as well as binding of radiolabelled ligands to receptors and immunohistofluorescence of tyrosine hydroxylase. These confirm unilateral destruction of dopamine innervation of the caudate-putamen in hemiparkinsonian monkeys and increased D2 receptors in this area in these animals. PET scanning with 18F-DOPA is being planned to follow the degeneration-regeneration process in monkey brain after MPTP treatment. The mechanisms of toxicity involve metabolism to its pyridium derivative (MPP+) which is accumulated in dopaminergic neurones. Toxicity of MPP+ may involve free radicals and affinity to neuromelanin. In mice, drugs which potentiate (e.g., copper chelators) or alleviate (e.g., reducing agents) MPTP toxicity provide evidence for involvement of superoxide free-radicals in causing the toxic damage to the amine accumulating neurones.