Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec (QC), Canada; Faculty of Pharmacy, Laval University, Quebec (QC), Canada.
Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec (QC), Canada; Faculty of Pharmacy, Laval University, Quebec (QC), Canada.
Exp Neurol. 2014 Jun;256:105-16. doi: 10.1016/j.expneurol.2013.01.024. Epub 2013 Jan 27.
The treatment of motor symptoms of Parkinson disease (PD) with the dopamine (DA) precursor, l-3,4-dihydroxyphenylalanine (l-DOPA) introduced 50years ago still remains a very effective medication. However, involuntary movements termed l-DOPA-induced dyskinesias (LID) appear in the vast majority of PD patients after chronic treatment and may become disabling. Once they appeared, the first dose after a several-weeks drug holiday will trigger them again, showing that l-DOPA has permanently or persistently modified the brain response to DA. LID are very difficult to manage and no drug is yet approved for dyskinesias, aside from a modest benefit with amantadine. New drugs are needed for PD to alleviate parkinsonian symptoms without inducing dyskinesias. Hence, animal models have been developed to seek the mechanisms involved in LID and new drug targets. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was discovered as a contamination of a derivative of heroin taken by drug users and produced similar motor symptoms as idiopathic PD. Since then, MPTP is used extensively to model PD and LID in non-human primates and mice in addition to the classical PD model in rats with a 6-hydroxydopamine (6-OHDA) lesion. This article reviews rodent and non-human primate models of PD that reproduce motor complications induced by DA replacement therapy. Moreover, key biochemical changes in the brain of post-mortem PD patients with LID will be compared to those observed in animal models. Finally, the translational usefulness of drugs found to treat LID in animal models will be compared to their clinical activities.
50 年前，采用多巴胺（DA）前体左旋 3,4-二羟基苯丙氨酸（l-DOPA）治疗帕金森病（PD）的运动症状仍然是一种非常有效的药物。然而，在慢性治疗后，绝大多数 PD 患者会出现不自主运动，即 l-DOPA 诱导的运动障碍（LID），并且可能导致残疾。一旦出现，在几周的停药期后第一次服药就会再次引发它们，表明 l-DOPA 已经永久性或持续性地改变了大脑对 DA 的反应。LID 非常难以管理，除了金刚烷胺有适度的益处外，目前还没有药物批准用于治疗运动障碍。需要新的药物来缓解 PD 患者的帕金森症状而不引起运动障碍。因此，已经开发出动物模型来寻找与 LID 相关的机制和新的药物靶点。神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）被发现是吸毒者服用的海洛因衍生物的污染物，可产生与特发性 PD 相似的运动症状。从那时起，MPTP 被广泛用于除了用 6-羟多巴胺（6-OHDA）损伤制作的经典 PD 大鼠模型之外，在非人类灵长类动物和小鼠中模拟 PD 和 LID。本文综述了可复制 DA 替代疗法引起的运动并发症的 PD 啮齿动物和非人类灵长类动物模型。此外，将比较有 LID 的 PD 患者死后大脑中的关键生化变化与在动物模型中观察到的变化。最后，将比较在动物模型中发现的治疗 LID 的药物的转化用途与其临床活性。
