Universitat de Barcelona, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Unitat de Farmacologia I Farmacognòsia, Facultat de Farmàcia , Barcelona, Avda/Joan XXIII , Spain
Expert Opin Investig Drugs. 2014 Aug;23(8):1165-79. doi: 10.1517/13543784.2014.931370. Epub 2014 Jun 24.
A major unresolved issue in the Parkinson's disease (PD) treatment is the development of l-DOPA-induced dyskinesias (LIDs) as a side effect of chronic L-DOPA administration. Currently, LIDs are managed in part by reducing the L-DOPA dose or by the administration of amantadine. However, this treatment is only partially effective. A potential strategy, currently under investigation, is the coadministration of metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) and L-DOPA; a treatment that results in the improvement of dyskinesia symptoms and that permits reductions in l-DOPA dosage frequency.
The authors examine the role of mGluR5 in the pathophysiology of PD and the potential use of mGluR5 NAM as an adjuvant therapy together with a primary treatment with L-DOPA. Specifically, the authors look at the mavoglurant therapy and the evidence presented through preclinical and clinical trials.
Interaction between mGluR5 NAM and L-DOPA is an area of interest in PD research as concomitant treatment results in the improvement of LID symptoms in humans, thus enhancing the patient's quality of life. However, few months ago, Novartis decided to discontinue clinical trials of mavoglurant for the treatment of LID, due to the lack of efficacy demonstrated in trials NCT01385592 and NCT01491529, although no safety concerns were involved in this decision. Nevertheless, the potential application of mGluR5 antagonists as neuroprotective agents must be considered and further studies are warranted to better investigate their potential.
在帕金森病（PD）的治疗中，一个未解决的主要问题是由于慢性左旋多巴给药引起的左旋多巴诱导的运动障碍（LIDs）作为一种副作用。目前，通过减少左旋多巴剂量或给予金刚烷胺部分管理 LIDs。然而，这种治疗方法仅部分有效。目前正在研究的一种潜在策略是代谢型谷氨酸受体 5（mGluR5）负变构调节剂（NAM）与左旋多巴联合给药；这种治疗方法可以改善运动障碍症状，并允许减少左旋多巴剂量的频率。
作者研究了 mGluR5 在 PD 病理生理学中的作用，以及 mGluR5 NAM 作为与左旋多巴联合治疗的辅助治疗的潜在用途。具体来说，作者研究了 mavoglurant 治疗以及通过临床前和临床试验提出的证据。
mGluR5 NAM 与左旋多巴的相互作用是 PD 研究的一个关注领域，因为联合治疗可改善人类 LID 症状，从而提高患者的生活质量。然而，几个月前，由于在临床试验 NCT01385592 和 NCT01491529 中未显示出疗效，诺华决定停止 mavoglurant 治疗 LID 的临床试验，尽管该决定不涉及任何安全性问题。尽管如此，仍必须考虑将 mGluR5 拮抗剂作为神经保护剂的潜在应用，并需要进一步的研究来更好地研究它们的潜力。
