Van Kampen Jackalina M, Robertson Harold A
Neurodyn Life Sciences, NRC Building, 550 University Ave., Charlottetown, PE C1A 4P3 Canada.
Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, PE C1A 4P3 Canada.
EPMA J. 2017 Sep 4;8(3):261-271. doi: 10.1007/s13167-017-0114-6. eCollection 2017 Sep.
Parkinson's disease (PD) is a neurodegenerative disorder, classically considered a movement disorder. A great deal is known about the anatomical connections and neuropathology and pharmacological changes of PD, as they relate to the loss of dopaminergic function and the appearance of cardinal motor symptoms. Our understanding of the role of dopamine in PD has led to the development of effective pharmacological treatments of the motor symptoms in the form of dopamine replacement therapy using levodopa and dopaminergic agonists. Much of the information concerning these drug treatments has been obtained using classical neurotoxic models that mimic dopamine depletion (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPTP, 6-hydroxydopamine, reserpine). However, PD is more than a disorder of the nigrostriatal dopamine pathway. Our understanding of the neuropathology of PD has undergone massive changes, with the discovery that mutations in α-synuclein cause a familial form of PD and that PD pathology may spread, affecting multiple neurotransmitter systems and brain regions. These new developments in our understanding of PD demand that we reconsider our animal models. While classic neurotoxin models have been useful for the development of effective symptomatic treatments for motor manifestations, the paucity of a valid animal model exhibiting the progressive development of multiple key features of PD pathophysiology and phenotype has impeded the search for neuroprotective therapies, capable of slowing or halting disease progression.
What characteristics would a good animal model of human PD have? In so much as is possible, a good model would exhibit as many behavioral, anatomical, biochemical, immunological, and pathological changes as are observed in the human condition, developing progressively, with clear, identifiable biomarkers along the way. Here, we review the BSSG rat model of PD, a novel environmental model of PD, with strong construct, face, and predictive validity. This model offers an effective tool for the screening of preventive therapies that may prove to be more predictive of their effects in human patients.
帕金森病（PD）是一种神经退行性疾病，传统上被认为是一种运动障碍。人们对PD的解剖学联系、神经病理学和药理学变化了解甚多，这些变化与多巴胺能功能丧失和主要运动症状的出现有关。我们对多巴胺在PD中作用的理解促使了以左旋多巴和多巴胺能激动剂进行多巴胺替代疗法的形式，开发出有效的运动症状药物治疗方法。关于这些药物治疗的许多信息是通过使用模拟多巴胺耗竭的经典神经毒性模型获得的（例如，1-甲基-4-苯基-1,2,3,6-四氢吡啶或MPTP、6-羟基多巴胺、利血平）。然而，PD不仅仅是黑质纹状体多巴胺通路的疾病。随着α-突触核蛋白突变导致家族性PD的发现以及PD病理可能扩散，影响多个神经递质系统和脑区，我们对PD神经病理学的理解发生了巨大变化。我们对PD理解的这些新进展要求我们重新审视我们的动物模型。虽然经典神经毒素模型对于开发有效的运动表现症状性治疗方法很有用，但缺乏一个有效的动物模型来展现PD病理生理学和表型的多个关键特征的渐进发展，这阻碍了对能够减缓或阻止疾病进展的神经保护疗法的探索。
本文对预测性、预防性和个性化医学的意义：人类PD的良好动物模型应具备哪些特征？一个好的模型应尽可能多地展现出在人类疾病中观察到的行为、解剖、生化、免疫和病理变化，逐步发展，并在此过程中有清晰、可识别的生物标志物。在此，我们回顾了PD的BSSG大鼠模型，这是一种新型的PD环境模型，具有强大的结构效度、表面效度和预测效度。该模型为筛选预防性疗法提供了一个有效工具，这些疗法可能在人类患者中更能预测其效果。
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