Nishi K, Kondo T, Narabayashi H
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
No To Shinkei. 1987 Jul;39(7):663-72.
N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been reported to cause chronic Parkinsonism in humans, primates, and long lasting striatal dopamine depletion in mice. Acute animal models thus produced closely resemble Parkinson's disease. There are, however, two major differences. The one is a lack of Lewy bodies and the other is that norepinephrine system is relatively well preserved in the model. So the acute animal model is better considered a nigrostriatal dopamine deficiency model. We have produced another model by adding N-2-chloroethyl-N-ethyl-2-bromobenzyl-amine (DSP4) to MPTP. This material is known to produce selective destruction of norepinephrine terminal in the central nervous system as well as in the periphery. Both norepinephrine system and dopamine system are severely depressed in this model, and the functional role of norepinephrine system was investigated by comparing two models. 90 male C57 black mice weighing 20-25 grams were used. MPTP (Aldrich) was dissolved in sterile distilled water with 5% ethanol solution. Experimental animals were divided into three groups. i) control group; in this group animals received vehicles alone. ii) MPTP group; in this group, mice received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days, thus total doses of MPTP was 300 mg/kg. iii) MPTP & DSP4 group; in this group animals received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days and at the last day of MPTP injection they received DSP4 50 mg/kg i.p.. 7 to 14 days after the last injection of MPTP both treated and control mice received an intraperitoneal injection of L-DOPA (200 mg/kg & aromatic L-amino acid decarboxylase mg/kg) and the effect of this drug on three groups were investigated by using behavioral, biochemical and histofluorescence method. Histofluorescence studies by GA-FAS method revealed severe reduction of nigrostriatal dopamine in MPTP treated mice. Mesolimbic and mesocortical dopamine systems seemed relatively preserved. There was no apparent changes in locus coeruleus norepinephrine system. In MPTP & DSP4 treated mice marked reduction of norepinephrine terminal fluorescence as well as nigrostriatal dopamine system was observed. Chemical analysis of norepinephrine and dopamine by HPLC confirmed histofluorescence studies. Behavioral studies were analyzed by Automex locomotor activity meter. Marked increase of locomotor activity was observed in MPTP treated mice after L-DOPA administration.(ABSTRACT TRUNCATED AT 400 WORDS)
据报道，N-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）可导致人类、灵长类动物出现慢性帕金森症，并使小鼠纹状体多巴胺长期耗竭。由此产生的急性动物模型与帕金森病极为相似。然而，存在两个主要差异。一是缺乏路易小体，另一个是该模型中去甲肾上腺素系统相对保存完好。因此，急性动物模型更好地被视为黑质纹状体多巴胺缺乏模型。我们通过向MPTP中添加N-2-氯乙基-N-乙基-2-溴苄胺（DSP4）建立了另一种模型。已知该物质可导致中枢神经系统以及外周的去甲肾上腺素末梢选择性破坏。在这个模型中，去甲肾上腺素系统和多巴胺系统均严重受损，通过比较两种模型来研究去甲肾上腺素系统的功能作用。使用了90只体重20 - 25克的雄性C57黑小鼠。MPTP（Aldrich）溶解于含5%乙醇溶液的无菌蒸馏水中。实验动物分为三组。i）对照组；该组动物仅接受溶剂。ii）MPTP组；在该组中，小鼠连续10天每天腹腔注射30毫克/千克的MPTP，因此MPTP的总剂量为300毫克/千克。iii）MPTP&DSP4组；在该组中，动物连续10天每天腹腔注射30毫克/千克的MPTP，在MPTP注射的最后一天，它们腹腔注射50毫克/千克的DSP4。在最后一次注射MPTP后7至14天，处理组和对照组小鼠均接受腹腔注射左旋多巴（200毫克/千克和芳香族L-氨基酸脱羧酶毫克/千克），并通过行为、生化和组织荧光法研究该药物对三组的影响。通过GA - FAS方法进行的组织荧光研究显示，MPTP处理的小鼠黑质纹状体多巴胺严重减少。中脑边缘和中脑皮质多巴胺系统似乎相对保存完好。蓝斑去甲肾上腺素系统没有明显变化。在MPTP&DSP4处理的小鼠中，观察到去甲肾上腺素末梢荧光以及黑质纹状体多巴胺系统明显减少。通过高效液相色谱法对去甲肾上腺素和多巴胺进行化学分析证实了组织荧光研究结果。行为研究通过Automex运动活动计进行分析。在MPTP处理的小鼠给予左旋多巴后，观察到运动活动明显增加。（摘要截选至400字）
