Comparative Medicine and Animal Resource Centre, McGill University, Montreal, QC, Canada.
Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, Montreal, QC, H3A 2B4, Canada.
J Neural Transm (Vienna). 2020 Jul;127(7):1023-1029. doi: 10.1007/s00702-020-02185-z. Epub 2020 Apr 3.
In recent studies performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease (PD), we have demonstrated that activation of the metabotropic glutamate 2 (mGlu) receptor with the orthosteric agonist (OA) LY-354,740 and the positive allosteric modulator (PAM) LY-487,379 is effective at alleviating both dyskinesia and psychosis-like behaviours (PLBs) triggered by the administration of L-3,4-dihydroxyphenylalanine (L-DOPA). Because mGlu OAs and PAMs bind to different sites on the receptor, we hypothesised that greater reductions of dyskinesia and PLBs would be obtained upon concurrent administration of LY-354,740 and LY-487,379. In experiments performed in six MPTP-lesioned marmosets, we administered LY-354,740 (0.1 mg/kg), LY-487,379 (1 mg/kg), LY-354,740 (0.1 mg/kg) + LY-487,379 (1 mg/kg), or vehicle, in combination with L-DOPA and determined the effect of each treatment on dyskinesia, PLBs, and parkinsonism. When compared to vehicle, LY-354,740 and LY-487,379, administered alone or concurrently, significantly reduced dyskinesia. The combination LY-354,740 + LY-487,379 provided mild additional benefit when compared to LY-487,379 alone, but not compared to LY-354,740. For PLBs, when compared to vehicle treatment, LY-354,740, LY-487,379, and combination thereof all alleviated the abnormal behaviours, but the combination LY-354,740 + LY-487,379 did not provide greater relief than either drug alone. The anti-parkinsonian effect of L-DOPA was not altered by any of the treatments. Our results provide further evidence that mGlu activation might be a novel approach to treat L-DOPA-induced dyskinesia and dopaminergic psychosis in PD. However, they do not suggest that greater therapeutic effect would be achieved upon combining an mGlu OA and an mGlu PAM.
在最近进行的 1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病(PD)恒河猴模型的研究中,我们已经证明,使用正构激动剂(OA)LY-354,740 和正变构调节剂(PAM)LY-487,379 激活代谢型谷氨酸 2(mGlu)受体可有效缓解 L-3,4-二羟基苯丙氨酸(L-DOPA)给药引发的运动障碍和类精神病行为(PLBs)。因为 mGlu OAs 和 PAMs 结合在受体的不同部位,我们假设同时给予 LY-354,740 和 LY-487,379 会导致运动障碍和 PLBs 得到更大程度的缓解。在六只 MPTP 诱导的恒河猴中进行的实验中,我们给予 LY-354,740(0.1mg/kg)、LY-487,379(1mg/kg)、LY-354,740(0.1mg/kg)+LY-487,379(1mg/kg)或载体,与 L-DOPA 联合使用,并确定每种治疗方法对运动障碍、PLBs 和帕金森病的影响。与载体相比,LY-354,740 和 LY-487,379 单独或联合使用时,均可显著减少运动障碍。与 LY-487,379 相比,LY-354,740+LY-487,379 的联合使用提供了轻度的额外益处,但与 LY-354,740 相比则没有。对于 PLBs,与载体治疗相比,LY-354,740、LY-487,379 和两者的联合均缓解了异常行为,但 LY-354,740+LY-487,379 的联合使用并未提供比单独使用任何一种药物更大的缓解作用。L-DOPA 的抗帕金森病作用不受任何治疗的影响。我们的结果进一步证明,mGlu 激活可能是治疗 PD 中 L-DOPA 诱导的运动障碍和多巴胺能精神病的一种新方法。然而,它们并没有表明,联合使用 mGlu OA 和 mGlu PAM 会获得更大的治疗效果。