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L-Dopa induced dyskinesias in Parkinsonian mice: Disease severity or L-Dopa history

机译：L-多巴诱发帕金森病小鼠的运动障碍：疾病严重程度或L-多巴病史

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In Parkinson's disease, the efficacy of L-Dopa treatment changes over time, as dyskinesias emerge with previously beneficial doses. Using MitoPark mice, that models mitochondrial failure in dopamine (DA) neurons and mimics the progressive loss of dopamine observed in Parkinson's disease, we found that the severity of DA denervation and associated adaptations in striatal neurotransmission at the time of initiation of L-Dopa treatment determines development of L-Dopa induced dyskinesias. We treated 20-week, and 28-week old MitoPark mice with L-Dopa (10 mg/kg i.p. twice a day) and found locomotor responses to be significantly different. While all MitoPark mice developed sensitization to L-Dopa treatment over time, 28-week old MitoPark mice with extensive striatal DA denervation developed abnormal involuntary movements rapidly and severely after starting L-Dopa treatment, as compared to a more gradual escalation of movements in 20-week old animals that started treatment at earlier stages of degeneration. Our data support that it is the extent of loss of DA innervation that determines how soon motor complications develop with L-Dopa treatment. Gene array studies of striatal neurotransmitter receptors revealed changes in mRNA expression levels for DA, serotonin, glutamate and GABA receptors in striatum of 28-week old MitoPark mice. Our results support that delaying L-Dopa treatment until Parkinson's disease symptoms become more severe does not delay the development of L-Dopa-induced dyskinesias. MitoPark mice model genetic alterations known to impair mitochondrial function in a subgroup of Parkinson patients and provide a platform in which to study treatments to minimize the development of dyskinesia. (C) 2015 The Authors. Published by Elsevier B.V.
机译：在帕金森氏病中，L-Dopa治疗的疗效会随时间而改变，因为运动障碍会以先前有益的剂量出现。使用MitoPark小鼠模拟多巴胺（DA）神经元的线粒体衰竭并模仿帕金森氏病中观察到的多巴胺的进行性丧失，我们发现在L-Dopa治疗开始时，DA神经支配的严重程度和纹状体神经传递中的相关适应性确定左旋多巴诱发的运动障碍的发展。我们用L-Dopa（每天两次，每次10 mg / kg腹腔注射）治疗20周和28周的MitoPark小鼠，发现运动反应显着不同。尽管随着时间的推移，所有MitoPark小鼠都对L-Dopa治疗产生了敏感性，但开始L-Dopa治疗后，具有广泛纹状体DA去神经支配的28周龄MitoPark小鼠迅速且严重地出现了异常的不自主运动，而在20年代运动逐渐加剧在退化的较早阶段开始治疗的一周龄动物。我们的数据表明，DA神经支配的丧失程度决定了L-Dopa治疗多久会导致运动并发症。纹状体神经递质受体的基因阵列研究显示，在28周龄的MitoPark小鼠纹状体中，DA，血清素，谷氨酸和GABA受体的mRNA表达水平发生了变化。我们的结果支持延迟帕金森病症状变得更严重之前延迟L-Dopa的治疗不会延迟L-Dopa引起的运动障碍的发展。 MitoPark小鼠模型化了已知会损害帕金森病患者亚组中线粒体功能的遗传改变，并提供了一个平台来研究治疗方法以最大程度地减少运动障碍的发生。 （C）2015作者。由Elsevier B.V.发布

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