The mGluR5 Negative Allosteric Modulator Dipraglurant Reduces Dyskinesia in the MPTP Macaque Model
The mGluR5 Negative Allosteric Modulator Dipraglurant Reduces Dyskinesia in the MPTP Macaque Model
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DOI：
10.1002/mds.25920
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发表时间：
2014-07-01
影响因子：
8.6
通讯作者：
Poli, Sonia M.
中科院分区：
文献类型：
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作者：
Bezard, Erwan;Pioli, Elsa Y.;Poli, Sonia M.
背景：阻断代谢性谷氨酸受体5型（mGluR5）被认为是治疗帕金森病（PD）左旋多巴诱导的运动障碍（LID）的靶点。我们在金标准LID猕猴模型中评估了dipraglurant对LID的影响，dipraglurant是一种有效的选择性mGluR5受体阴性变构调节剂。方法：采用四向交叉、单剂量、对照研究方法，对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）猕猴LID模型进行3、10、30 mg/kg灌胃双氟化剂的实验。结果：左旋多巴对LID猕猴运动障碍有抑制作用，以30 mg/kg剂量效果最佳，左旋多巴的疗效无明显变化。结论：双氯丙嗪急性刺激对mptp -猕猴模型的舞蹈性和张力障碍性LID有效。双胍药代动力学变量与左旋多巴相似，提示在进一步的研究中，两种药物可以同时使用。(C) 2014国际帕金森和运动障碍学会
Background: Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model.Methods: Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8).Results: Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy.Conclusion: Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies. (C) 2014 International Parkinson and Movement Disorder Society