Pollard H B, Dhariwal K, Adeyemo O M, Markey C J, Caohuy H, Levine M, Markey S, Youdim M B
Laboratory of Cell Biology and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
FASEB J. 1992 Sep;6(12):3108-16. doi: 10.1096/fasebj.6.12.1521741.
Parkinson's disease has been modeled in humans, lower primates, and to a lesser extent in some other vertebrates by administration of the potent neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine). The MPTP model has thus drawn considerable attention as a system to search for anti-Parkinson's disease drugs, although the cost and scarcity of primates has limited extensive applications. We now report that a parkinsonian syndrome can be elicited in the common goldfish (Carassius auratus) by a single dose of MPTP. The syndrome is characterized by profound bradykinesia (slow movement), the full extent of which is reached 3 days after MPTP administration. The reduction in movement is paralleled by loss of dopamine and norepinephrine from the forebrain and midbrain and in other brain regions as well. The toxic oxidative product of MPTP, MPP+, is also accumulated predominantly in forebrain and midbrain, and pretreatment with the monoamine oxidase blocker tranylcypromine substantially reduces accumulation of the toxic metabolite. A barely perceptible coarseness in balance adjustment also occurs in treated animals. The MPTP-treated goldfish recover normal movement and normal brain monoamine levels within 10-13 days after administration of the drug. We interpret these and other data to indicate that MPTP can induce a Parkinson's disease-like syndrome in the goldfish that is similar in many aspects to the syndrome induced by MPTP in humans and other primates. This remarkable parallel may permit the goldfish to supplement expensive and scarce primates for the purpose of searching and screening neuroprotective drugs with specific relevance to Parkinson's disease.
通过给予强效神经毒素MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶），帕金森病已在人类、低等灵长类动物中建立了模型，在其他一些脊椎动物中也有一定程度的建模。因此，MPTP模型作为一种寻找抗帕金森病药物的系统引起了相当大的关注，尽管灵长类动物的成本和稀缺性限制了其广泛应用。我们现在报告，单次给予MPTP可在普通金鱼（Carassius auratus）中引发帕金森综合征。该综合征的特征是严重的运动迟缓（动作缓慢），在给予MPTP后3天达到最严重程度。运动减少伴随着前脑、中脑以及其他脑区多巴胺和去甲肾上腺素的丧失。MPTP的有毒氧化产物MPP +也主要在前脑和中脑积累，用单胺氧化酶阻滞剂反苯环丙胺预处理可显著减少有毒代谢物的积累。在接受治疗的动物中还会出现几乎难以察觉的平衡调节粗糙现象。在给予药物后10 - 13天内，经MPTP处理的金鱼恢复正常运动和正常脑单胺水平。我们对这些及其他数据的解读表明，MPTP可在金鱼中诱发一种帕金森病样综合征，在许多方面与MPTP在人类和其他灵长类动物中诱发的综合征相似。这种显著的相似性可能使金鱼能够补充昂贵且稀缺的灵长类动物，用于寻找和筛选与帕金森病具有特定相关性的神经保护药物。
