Carvey Paul M, Punati Ashok, Newman Mary B
Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA.
Cell Transplant. 2006;15(3):239-50. doi: 10.3727/000000006783981990.
Animal models have been an essential tool for researchers and clinicians in their efforts to study and treat Parkinson's disease (PD). Thus, the various ways 6-hydroxydopamine is employed, the use of MPTP in rodents and nonhuman primates, the prenatal exposure to bacterial endotoxin, the postnatal exposure to environmental toxins such as paraquat and rotenone, the assessment of dopamine (DA) neurons in genetic knockout mouse, and even the behavioral analysis of fruit flies and worms have added significantly to our knowledge base of PD--or have they? Are these animal models manifesting a true model of PD? Have the 7786 published studies (to date) on PD with animal models led to a clearer understanding of its etiology, treatment, or progression? In this review we critically assess this question. We begin with a succinct history of the major contributions, which have led to the current animal models of PD. We then evaluate the primary issue of the progressive loss of DA neurons, which, except for a few studies, has not been addressed in animal models of PD, even though this is the major pathological characteristic of the disease. Lastly, we discuss the possibility that more than one risk factor for PD may be necessary to develop an animal model that shows synergy--the progressive loss of DA neurons. Thus, the multiple hit hypothesis of PD-that is, the effect of more then one risk factor-may be the start of new era in animal models of PD that is one step closer to mimicking the pathology of PD in humans.
动物模型一直是研究人员和临床医生研究和治疗帕金森病（PD）的重要工具。因此，6-羟基多巴胺的各种使用方式、在啮齿动物和非人类灵长类动物中使用MPTP、产前暴露于细菌内毒素、产后暴露于百草枯和鱼藤酮等环境毒素、对基因敲除小鼠中多巴胺（DA）神经元的评估，甚至果蝇和蠕虫的行为分析，都极大地丰富了我们关于PD的知识库——真的是这样吗？这些动物模型真的能体现PD的真实模型吗？迄今为止发表的7786项关于PD动物模型的研究是否让我们对其病因、治疗或进展有了更清晰的认识？在这篇综述中，我们将批判性地评估这个问题。我们首先简要回顾一下主要贡献的历史，这些贡献促成了目前的PD动物模型。然后，我们评估DA神经元逐渐丧失这一主要问题，除了少数研究外，PD动物模型中尚未涉及这一问题，尽管这是该疾病的主要病理特征。最后，我们讨论了可能需要不止一个PD风险因素才能建立一个显示协同作用——DA神经元逐渐丧失的动物模型。因此，PD的多重打击假说——即不止一个风险因素的影响——可能是PD动物模型新时代的开端，使我们离模拟人类PD的病理学又近了一步。
