Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada.
Comparative Medicine & Animal Resource Centre, McGill University, Montreal, QC, Canada.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Nov;397(11):8917-8924. doi: 10.1007/s00210-024-03215-3. Epub 2024 Jun 11.
There is mounting evidence that positive allosteric modulation of metabotropic glutamate type 2 receptors (mGluR) is an efficacious approach to reduce the severity of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, psychosis-like behaviours (PLBs), while conferring additional anti-parkinsonian benefit. However, the mGluR positive allosteric modulators (PAMs) tested so far, LY-487,379 and CBiPES, share a similar chemical scaffold. Here, we sought to assess whether similar benefits would be conferred by a structurally-distinct mGluR PAM, biphenylindanone A (BINA). Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and PLBs were administered L-DOPA with either vehicle or BINA (0.1, 1, and 10 mg/kg) in a randomised within-subject design and recorded. Behaviour was analysed by a blinded rater who scored the severity of each of parkinsonism, dyskinesia and PLBs. When added to L-DOPA, BINA 0.1 mg/kg, 1 mg/kg, and 10 mg/kg all significantly reduced the severity of global dyskinesia, by 40%, 52% and 53%, (all P < 0.001) respectively. BINA similarly attenuated the severity of global PLBs by 35%, 48%, and 50%, (all P < 0.001) respectively. Meanwhile, BINA did not alter the effect of L-DOPA on parkinsonism exhibited by the marmosets. The results of this study provide incremental evidence of positive allosteric modulation of mGluR as an effective therapeutic strategy for alleviating dyskinesia and PLBs, without hindering the anti-parkinsonian action of L-DOPA. Furthermore, this therapeutic benefit does not appear to be confined to a particular chemical scaffold.
越来越多的证据表明,代谢型谷氨酸受体 2(mGluR)的正变构调节是一种有效的方法,可以减轻 L-3,4-二羟基苯丙氨酸(L-DOPA)诱导的运动障碍、类精神病行为(PLBs)的严重程度,同时提供额外的抗帕金森益处。然而,迄今为止测试的 mGluR 正变构调节剂(PAMs),LY-487,379 和 CBiPES,具有相似的化学结构。在这里,我们试图评估结构不同的 mGluR PAM,双苯并吲哚酮 A(BINA)是否会带来类似的益处。六只患有运动障碍和 PLBs 的 1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)损伤的狨猴,以随机、自身对照的方式接受 L-DOPA 与载体或 BINA(0.1、1 和 10mg/kg)联合治疗,并进行记录。行为由一名盲法评分者进行分析,他对帕金森病、运动障碍和 PLBs 的严重程度进行评分。当添加到 L-DOPA 时,BINA 0.1mg/kg、1mg/kg 和 10mg/kg 分别显著降低了整体运动障碍的严重程度,分别降低了 40%、52%和 53%(均 P<0.001)。BINA 同样分别降低了整体 PLBs 的严重程度,降低了 35%、48%和 50%(均 P<0.001)。同时,BINA 并未改变 L-DOPA 对狨猴帕金森病的作用。这项研究的结果提供了代谢型谷氨酸受体 2 的正变构调节作为减轻运动障碍和 PLBs 的有效治疗策略的额外证据,而不会阻碍 L-DOPA 的抗帕金森作用。此外,这种治疗益处似乎并不局限于特定的化学结构。
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