Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul, 02447, Republic of Korea.
Integrative Parkinson's Disease Research Group, Acupuncture & Meridian Science Research Center, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul, 02447, Republic of Korea.
Mol Neurobiol. 2019 Apr;56(4):2408-2423. doi: 10.1007/s12035-018-1194-6. Epub 2018 Jul 20.
Although L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the most effective medication for treating Parkinson's disease (PD) motor symptoms, its prolonged administration causes several adverse effects, including dyskinesia. To identify the mechanisms underlying the effects of acupuncture on L-DOPA-induced dyskinesia (LID), antidyskinetic effects of acupuncture were investigated in two mouse models of PD. Acupuncture stimulation at GB34 alleviated abnormal involuntary movements (AIMs) in Pitx3-deficient aphakia mice (ak/ak) following L-DOPA administration and these effects were reproduced in 6-hydroxydopamine (6-OHDA)-lesioned mice with LID. A transcriptome analysis of the hypothalamus revealed pro-melanin-concentrating hormone (Pmch) gene was highly expressed in acupuncture-treated mouse from ak/ak model of LID as well as 6-OHDA model of LID. Acupuncture combined with the administration of MCH receptor antagonist did not have any beneficial effects on dyskinesia in L-DOPA-injected ak/ak mice, but the intranasal administration of MCH attenuated LID to the same degree as acupuncture in both ak/ak and 6-OHDA mice with LID. A gene expression profile with a hierarchical clustering analysis of the dyskinesia-induced ak/ak mouse brain revealed an association between the mechanisms underlying acupuncture and MCH. Additionally, altered striatal responses to L-DOPA injection were observed after prolonged acupuncture and MCH treatments, which suggests that these treatment modalities influenced the compensatory mechanisms of LID. In summary, present study demonstrated that acupuncture decreased LID via hypothalamic MCH using L-DOPA-administered ak/ak and 6-OHDA mouse models and that MCH administration resulted in novel antidyskinetic effects in these models. Thus, acupuncture and MCH might be valuable therapeutic candidates for PD patients suffering from LID.
虽然 L-3,4-二羟基苯丙氨酸（L-DOPA）是目前治疗帕金森病（PD）运动症状最有效的药物，但长期使用会导致多种不良反应，包括运动障碍。为了确定针灸对 L-DOPA 诱导的运动障碍（LID）的影响机制，我们在两种 PD 小鼠模型中研究了针灸的抗运动障碍作用。GB34 针灸刺激可减轻 L-DOPA 给药后 Pitx3 缺失的无眼畸形小鼠（ak/ak）的异常不自主运动（AIMs），并且这些作用在 LID 的 6-羟多巴胺（6-OHDA）损伤小鼠中得到再现。下丘脑的转录组分析显示，在 ak/ak 模型和 6-OHDA 模型的 LID 中，促黑素集中激素（Pmch）基因在接受针灸治疗的小鼠中高度表达。在 L-DOPA 注射的 ak/ak 小鼠中，MCH 受体拮抗剂与针灸联合给药对运动障碍没有任何有益作用，但 MCH 鼻内给药对 ak/ak 和 6-OHDA 小鼠的 LID 具有与针灸相同的缓解作用。对 ak/ak 小鼠脑运动障碍诱导的基因表达谱进行层次聚类分析显示，针灸和 MCH 的作用机制之间存在关联。此外，在长期针灸和 MCH 治疗后观察到纹状体对 L-DOPA 注射的反应发生改变，这表明这些治疗方式影响了 LID 的代偿机制。总之，本研究表明，针灸通过 L-DOPA 给药的 ak/ak 和 6-OHDA 小鼠模型中的下丘脑 MCH 降低了 LID，并且 MCH 给药导致这些模型中出现新的抗运动障碍作用。因此，针灸和 MCH 可能是患有 LID 的 PD 患者的有价值的治疗候选药物。
