MPTP TOXICITY AND ANIMAL MODELS OF PARKINSON'S DISEASE

MPTP 毒性和帕金森病动物模型

• 批准号: 3945311
• 负责人: I J KOPIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3945311
• 关键词: Parkinson's disease; disease /disorder model; dopamine; free radicals; immunochemistry; immunofluorescence technique; innervation; model design /development; nervous system regeneration; neural degeneration; neuropharmacology; neurotoxins; neurotransmitter metabolism; norepinephrine; positron emission tomography; pyridine; radiotracer; serotonin; toxin metabolism; tyrosine 3 monooxygenase

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin which causes selective destruction of dopaminergic neurones of the nigrostriatal 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) are used to evaluate agonists (which reverse the turning) and procedures which regenerate or replace by implantation dopamine-producing cells. Dopaminergic neurones and receptor changes have been demonstrated 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 has demonstrated the deficiency in dopamine formation and storage in the striatum of MPTP treated animals and the restoration of dopamine in transplants of fetal mesencephalic tissue. Tyrosine hydroxylase immunohistochemical studies of the results of tissue implants suggest stimulation of sprouting of surviving dopaminergic neurones rather than fiber ingrowth from the implant as the cause of functional recovery. There are also functional restorations of local cerebral glucose utilization (LCGU) in areas of the cortex and striatum in which LCGU is depressed by MPTP. Using LCGU to examine responses to DOPA, it was found that supersensitivity was evident in that LCGU was markedly elevated in MPTP-treated, but not in normal monkeys by L-DOPA. In hemiparkinsonian monkeys, the ocular dominance columns could be distinguished and those innervated by the MPTP treated-eye reacted to L-DOPA in a similar hyperactive manner, suggesting retinal dopamine receptor supersensitivity.

1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）是一种 一种能选择性破坏多巴胺能神经的神经毒素 神经元的黑质纹状体通路的猴子，但较少 在需要更高剂量并影响其他区域的小鼠中具有特异性 也 通过输液建立了偏侧帕金森病模型 注射到猴子的颈内动脉。 的 行为效应（转向病变侧） 用于评估激动剂（逆转逆转）， 通过植入再生或替代的手术 产生多巴胺的细胞 多巴胺能神经元和受体 已经使用生物化学技术证明了这些变化， 多巴胺、去甲肾上腺素和血清素的测量， 它们的代谢物以及放射性标记配体与 受体和酪氨酸羟化酶的荧光。 这些证实了多巴胺神经支配的单侧破坏， 帕金森病猴尾壳核和增加 D2受体在这些动物的这个区域。 PET扫描， 18F-DOPA已经证明了多巴胺的缺乏 在MPTP处理的动物的纹状体中的形成和储存 以及胎儿移植中多巴胺的恢复 中脑组织 酪氨酸羟化酶免疫组织化学 对组织植入物结果的研究表明， 存活的多巴胺能神经元而不是纤维发芽 植入物的向内生长是功能恢复的原因。 局部脑葡萄糖也有功能性改变， 利用（LCGU）在皮质和纹状体的区域，其中 MPTP抑制LCGU。 使用LCGU检查响应 对多巴，发现超敏感性明显， MPTP治疗组LCGU明显升高，而正常对照组LCGU无明显变化。 用左旋多巴给猴子注射 在偏侧帕金森病猴中， 优势柱可以区分和那些支配 MPTP治疗眼对L-DOPA的反应类似于 过度活跃的方式，表明视网膜多巴胺受体 超敏感