An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates
An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates
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DOI：
10.1002/mds.27462
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发表时间：
2018-10-01
影响因子：
8.6
通讯作者：
Conquet, Francois
中科院分区：
文献类型：
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作者：
Charvin, Delphine;Di Paolo, Therese;Conquet, Francois
背景：左旋多巴仍然是PD的金标准治疗。然而，随着疾病的进展，它变得不那么有效，并产生使人衰弱的副作用，如运动波动和左旋多巴诱导的运动障碍。代谢型谷氨酸受体4的调制代表了一个有前途的抗帕金森病的方法与左旋多巴相结合，但它还没有被证明在灵长类动物。目的：我们研究了代谢型谷氨酸受体4的新型正变构调节剂PXT 002331（foliglurax）是否可以减少灵长类动物模型中的帕金森症。方法：我们评估了PXT 002331在三种MPTP诱导的猕猴帕金森综合征模型中的治疗潜力。这些模型代表了疾病演变的三个不同阶段：早期阶段和晚期阶段，有和没有左旋多巴诱导的运动障碍。结果如下：作为左旋多巴的辅助药物，PXT 002331诱导了猕猴帕金森病运动症状的稳健和剂量依赖性逆转，包括运动迟缓、震颤、姿势和移动性。此外，PXT 002331强烈降低运动障碍的严重程度，因此对帕金森病运动障碍和左旋多巴诱导的运动障碍都具有治疗功效。还在猕猴中使用PET成像评估了PXT 002331的脑渗透，并且药效学分析支持PXT 002331的治疗效果中的靶点参与。结论：这项工作提供了一个证据，即代谢型谷氨酸受体4的正变构调节剂可以减轻帕金森病的运动症状和运动并发症的左旋多巴在灵长类动物。PXT 002331是同类药物中第一个进入IIa期临床试验的化合物。(c)2018国际帕金森和运动障碍协会
Background: Levodopa remains the gold-standard treatment for PD. However, it becomes less effective as the disease progresses and produces debilitating side effects, such as motor fluctuations and l-dopa-induced dyskinesia. Modulation of metabotropic glutamate receptor 4 represents a promising antiparkinsonian approach in combination with l-dopa, but it has not been demonstrated in primates. Objective: We studied whether a novel positive allosteric modulator of the metabotropic glutamate receptor 4, PXT002331 (foliglurax), could reduce parkinsonism in primate models. Methods: We assessed the therapeutic potential of PXT002331 in three models of MPTP-induced parkinsonism in macaques. These models represent three different stages of disease evolution: early stage and advanced stage with and without l-dopa-induced dyskinesia. Results: As an adjunct to l-dopa, PXT002331 induced a robust and dose-dependent reversal of parkinsonian motor symptoms in macaques, including bradykinesia, tremor, posture, and mobility. Moreover, PXT002331 strongly decreased dyskinesia severity, thus having therapeutic efficacy on both parkinsonian motor impairment and l-dopa-induced dyskinesia. PXT002331 brain penetration was also assessed using PET imaging in macaques, and pharmacodynamic analyses support target engagement in the therapeutic effects of PXT002331. Conclusions: This work provides a demonstration that a positive allosteric modulator of metabotropic glutamate receptor 4 can alleviate the motor symptoms of PD and the motor complications induced by l-dopa in primates. PXT002331 is the first compound of its class to enter phase IIa clinical trials. (c) 2018 International Parkinson and Movement Disorder Society