Histamine H3 receptor agonists reduce L-dopa-induced chorea, but not dystonia, in the MPTP-lesioned nonhuman primate model of Parkinson's disease
Histamine H3 receptor agonists reduce L-dopa-induced chorea, but not dystonia, in the MPTP-lesioned nonhuman primate model of Parkinson's disease
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DOI：
10.1002/mds.20828
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发表时间：
2006-06-01
影响因子：
8.6
通讯作者：
Brotchie, Jonathan M.
中科院分区：
文献类型：
--
作者：
Gomez-Ramirez, Jordi;Johnston, Tom H.;Brotchie, Jonathan M.
左旋多巴引起的运动障碍（LID）仍然是帕金森病治疗的主要并发症。 LID 的神经机制被认为涉及纹状体谷氨酸能神经传递的过度活跃，从而导致基底神经节输出区域的激活不足。组胺 H3 异质受体可以分别减少纹状体和黑质网状结构中谷氨酸和γ-氨基丁酸 (GABA) 的传输。因此，我们测试了组胺 H3 受体激动剂 immepip 和 imetit 是否可以减轻 MPTP 损伤的帕金森病狨猴模型中的 LID。与单独使用左旋多巴相比，immepip (1 mg/kg) 与左旋多巴 (15 mg/kg) 共同给药可显着减少总运动障碍。当运动障碍分别被评定为舞蹈病和肌张力障碍时，左旋多巴与immepip或imetit（均为10 mg/kg）共同给药可显着减少舞蹈病，但对肌张力障碍没有影响。 H3激动剂的抗运动障碍作用不伴随左旋多巴的抗帕金森病作用的改变。然而，与媒介物相比，immepip（10 mg/kg）作为单一疗法施用时，显着增加帕金森病残疾。总体而言，本研究获得的结果表明组胺 H3 受体可能参与左旋多巴诱导的帕金森病运动障碍的神经机制。 (c) 2006 年运动障碍协会。
L-dopa-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease. The neural mechanisms underlying LID are thought to involve overactivity of striatal glutamatergic neurotransmission, with resultant underactivation of the output regions of the basal ganglia. Histamine H3 heteroreceptors can reduce glutamate and gamma-aminobutyric acid (GABA) transmission in the striatum and substantia nigra reticulata, respectively. Thus, we tested whether the histamine H3 receptor agonists immepip and imetit can alleviate LID in the MPTP-lesioned marmoset model of Parkinson's disease. Coadministration of immepip (1 mg/kg) with L-dopa (15 mg/kg) was associated with significantly less total dyskinesia than L-dopa alone. When dyskinesia was separately rated as chorea and dystonia, coadministration Of L-dopa with either immepip or imetit (both 10 mg/kg) significantly reduced chorea but had no effect on dystonia. The antidyskinetic actions of the H3 agonists were not accompanied by alteration of the antiparkinsonian actions Of L-dopa. However, immepip (10 mg/kg), when administered as monotherapy, significantly increased parkinsonian disability compared to vehicle. Overall, the results obtained in this study suggest that histamine H3 receptors may be involved in the neural mechanisms underlying L-dopa-induced dyskinesia in Parkinson's disease. (c) 2006 Movement Disorder Society.