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浙江大学学报（农业与生命科学版）
浙江大学学报(农业与生命科学版)  2014, Vol. 40 Issue (3): 257-    DOI: 10.3785/j.issn.1008-9209.2013.10.281
生物科学与技术     
MPTP诱导慢性帕金森病恒河猴模型的初步建立
史良琴1,2, 罗启慧1,2, 曾文3, 龚立3, 程安春1,2, 毕凤君3, 曾利才3, 陈姗姗1,2, 陈正礼1,2*
（1.四川农业大学动物医学院,动物疾病与人类健康中心四川省重点实验室,四川 雅安625014；2.四川农业大学预防兽医研究所,成都611130;

3.四川普莱美生物科技有限公司/国家实验猕猴种源基地,四川 雅安625014）
Preliminary establishment of chronic Parkinsons disease in rhesus monkey model induced by injection of MPTP.
Shi Liangqin1,2, Luo Qihui1,2, Zeng Wen3, Gong Li3, Cheng Anchun1,2, Bi Fengjun3, Zeng Licai3, Chen Shanshan1,2, Chen Zhengli1,2*
(1. Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Yaan, Sichuan 625014, China; 2. Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; 3. Sichuan Primed Biological Technology Co., Ltd/National Experimental Macaque Reproduce Laboratory, Yaan, Sichuan 625014, China
)
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摘要： 拟建立一种不仅操作简便而且能较好模拟帕金森病（Parkinsons disease,PD）临床症状和病理进程的造模方法。选取健康老龄雌性恒河猴12只,随机分为实验组9只(进而按临床症状及行为学评分又分为3个亚组)和对照组3只,以0.2 mg/(kg·d)小剂量、多次重复肌内注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)来建立慢性PD恒河猴动物模型,对照组注射同等剂量的0.9%氯化钠溶液。每日于MPTP给药前后观察记录各组动物行为学表现各30 min。实验结束后,全部处死动物,采用免疫组织化学法检测黑质酪氨酸羟化酶（tyrosine hydroxylase,TH）和α-突触核蛋白（α-synuclein,α-syn）的分布与表达变化对模型进行验证。行为学结果显示,实验组动物出现3种不同程度的临床表现,根据其轻重,将其分为3个亚组；TH免疫组织化学结果显示,阳性物质主要分布于神经元胞质和突起内,与对照组相比,实验组中的第1、第2、第3亚组阳性总面积分别减少71.90%,61.90%,45.74%,差异有统计学意义（P<0.01）；α-syn免疫组织化学结果显示,阳性物质主要分布于神经突起内,其次为细胞间质,并在濒临死亡动物的黑质致密部检测到路易小体,实验各组动物黑质阳性总面积较对照组分别增加170.29%,137.82%,47.88%,差异有统计学意义（P<0.01）。上述结果表明,采用小剂量、多次重复肌内注射MPTP方式能够建立老龄恒河猴PD动物模型,该模型能够较好地模拟PD病人的临床症状和病理进程,是研究PD病因、发病机制、药物治疗及基因治疗较可靠的实验动物模型。
Abstract: Parkinsons disease (PD)  is a common and age-related progressive neurodegenerative disorder, and its pathogenesis is not yet entirely clear. The present study is to establish a model easy to control and better simulate the clinical symptoms, processes and pathological changes of PD patients, expecting to provide a foundation and platform service for pathogenesis and treatment research of Parkinsons disease. Twelve healthy aging female rhesus monkeys, divided into experimental group (nine  rhesus monkeys) and control group (three  rhesus monkeys) randomly, were respectively daily injected a small dose (0.2 mg/(kg·d)) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the same dose of saline by intramuscular injection for 45 days repeatedly. The behavioral manifestations of all monkeys were evaluated before and after the injection for 30 min, respectively. After sacrificed, the expression and distribution of tyroxine hydroxylase (TH) and α-synuclein  (α-syn)   in substantia nigra were studied by immunohistochemical method, and the immunopositive total area and average optical density were used to validate the model. The results of behavioral manifestations indicated that, experimental animals showed three different degrees of clinical manifestations and could be divided into three subgroups (three  animals each subgroup) according to the behavioral and clinical manifestations. The first subgroup showed typical behavioral manifestations of Parkinsons disease and one animal was in the moribund period. The activity, posture and bradypraxia of the third subgroup were slightly abnormal, and behavioral manifestations of the second subgroup were between the first and the third subgroup. However the control group did not show any abnormality.
The immunopositive productions of TH were mainly distributed at the cytoplasm and neurites. Compared with the control group, the positive cytoplasm and neurites of the first subgroup were severely reduced, even no positive production was observed in partial substantia nigra pars compacta; the   neuron  structure of the third  subgroup   was  mild blurred, and neurites were slightly shorter and fewer; the  positive productions and structure of the second subgroup were between the first
 and the third subgroup. Also compared with the control group, the positive total area of each group decreased by 71.90%, 61.90% and 45.74%, showing statistical significance (P<0.01).
The immunopositive productions of α-syn mainly distributed at neuritis, and also distributed at the intercellular substance, and Lewy bodies were detected at the substantia nigra pars compacta of the moribund animal. Compared with the control group, positive total area of each group increased by 170.29%,137.82% and 47.88%, showing statistical significance (P<0.01). The above results suggest  that the aging rhesus PD animal model can be established via small doses and repeated intramuscular injection of MPTP, and the PD model can better simulate the clinical behavioral manifestations, disease processes and pathological changes of PD patients, so the model is more reliable for etiology, pathogenesis, drug therapy and gene therapy of Parkinsons disease.    
出版日期: 2014-05-20
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程安春1
2
毕凤君3
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陈正礼1
2*
史良琴1
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罗启慧1
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引用本文:

史良琴1,2, 罗启慧1,2, 曾文3, 龚立3, 程安春1,2, 毕凤君3, 曾利才3, 陈姗姗1,2, 陈正礼1,2*. MPTP诱导慢性帕金森病恒河猴模型的初步建立[J]. 浙江大学学报(农业与生命科学版), 2014, 40(3): 257-.

Shi Liangqin1,2, Luo Qihui1,2, Zeng Wen3, Gong Li3, Cheng Anchun1,2, Bi Fengjun3, Zeng Licai3, Chen Shanshan1,2, Chen Zhengli1,2*. Preliminary establishment of chronic Parkinsons disease in rhesus monkey model induced by injection of MPTP.. Journal of Zhejiang University (Agriculture and Life Sciences), 2014, 40(3): 257-.

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http://www.zjujournals.com/agr/CN/10.3785/j.issn.1008-9209.2013.10.281    或    http://www.zjujournals.com/agr/CN/Y2014/V40/I3/257

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