Aix-Marseille Univ, Institut de Biologie du Développement de Marseille-Luminy (IBDML), UMR 7288, 13009 Marseille, France.
Neuropharmacology. 2013 Mar;66:158-69. doi: 10.1016/j.neuropharm.2012.03.022. Epub 2012 Apr 3.
Group III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l-DOPA, in particular the highly disabling l-DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naïve rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub-threshold doses of l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l-DOPA and a mGlu4 receptor PAM to reduce efficacious l-DOPA doses (generally known as l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
III 组代谢型谷氨酸 (mGlu) 受体位于基底神经节 (BG) 回路的突触前末梢，由于帕金森病 (PD) 中多巴胺耗竭而变得过度活跃。出于这个原因，III 组 mGlu 受体，特别是 mGlu4，已被认为是用于调节这些突触的非多巴胺能药物治疗的关键战略靶点，而不会产生众所周知的 l-DOPA 副作用，特别是高度致残的 l-DOPA 诱导的运动障碍 (LID)。在此，我们使用 Lu AF21934（一种新型选择性和穿透性 mGlu4 受体正变构调节剂 (PAM) 工具化合物）为该假说提供生理和功能支持。通过体外电生理记录，我们证明 Lu AF21934 抑制皮质纹状体突触传递，并增强了正构 mGlu4 受体优先激动剂 LSP1-2111 的作用。在未处理的大鼠中，Lu AF21934 剂量依赖性地（10 和 30mg/kg）缓解了氟哌啶醇引起的僵住。在半帕金森病大鼠（黑质致密部单侧 6-羟多巴胺损伤）中，在测试剂量（10 和 30mg/kg）下，Lu AF21934 单独使用并不影响运动不能。然而，当 Lu AF21934 与亚阈值剂量的 l-DOPA（1 和 5mg/kg）联合使用时，它以剂量依赖性方式协同缓解运动不能，并且显著降低了 LID 的发生率，而没有增加其严重程度。有趣的是，这些作用发生在 Lu AF21934 的脑游离浓度下，该浓度在体外筛选（钙通量和电生理测定）中显示出功能活性。这些结果支持联合治疗（l-DOPA 和 mGlu4 受体 PAM）用于帕金森病的临床应用的潜力，以减少有效的 l-DOPA 剂量（通常称为 l-DOPA 节约），同时保持对 PD 运动障碍的相同益处，同时最大限度地减少 LID 的发展。本文是特刊“代谢型谷氨酸受体”的一部分。
