Neurodegenerative Disease Group, Montreal Neurological Institute, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
Comparative Medicine & Animal Resource Centre, McGill University, Montreal, QC, Canada.
Neuropharmacology. 2018 Sep 1;139:61-67. doi: 10.1016/j.neuropharm.2018.06.038. Epub 2018 Jun 30.
Blockade of serotonin 2A (5-HT) receptors is regarded as an anti-dyskinetic and anti-psychotic strategy in Parkinson's disease (PD). However, the 5-HT antagonists tested so far exhibited affinity for other receptors, which might have played a role in their action. EMD-281,014 is the most selective 5-HT antagonist available, with approximately 2,000-fold selectivity over serotonin 2C (5-HT) receptors. EMD-281,014 was previously tested in the clinic and has high translational potential. In the present study, we assessed the effect of EMD-281,014 on dyskinesia and psychosis in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. We first determined the pharmacokinetic profile of EMD-281,014 in the marmoset, after which doses leading to clinically-relevant plasma levels (0.01, 0.03 and 0.1 mg/kg) or vehicle were administered to MPTP-lesioned marmosets, in combination with L-3,4-dihydroxyphenylalanine (l-DOPA). The effects of EMD-281,014 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were then evaluated. When added to l-DOPA, EMD-281,014 (0.03 and 0.1 mg/kg) reduced peak dose dyskinesia, by 41.8% and 54.5% (P < 0.05 and P < 0.001), when compared to l-DOPA/vehicle. EMD-281,014 (0.03 and 0.1 mg/kg) also significantly reduced the severity of peak dose PLBs, by 42.5% and 45.9% (P < 0.05 and P < 0.001), when compared to vehicle. The anti-dyskinetic and anti-psychotic effects of EMD-281,014 were achieved without interfering with l-DOPA anti-parkinsonian action. Our results suggest that highly-selective 5-HT receptor blockade with EMD-281,014 is an effective way to alleviate both dyskinesia and psychosis in PD, without adversely affecting parkinsonian disability.
5-羟色胺 2A（5-HT）受体阻断被认为是治疗帕金森病（PD）运动障碍和精神症状的一种策略。然而，到目前为止，测试的 5-HT 拮抗剂对其他受体具有亲和力，这可能在其作用中发挥了作用。EMD-281,014 是目前最具选择性的 5-HT 拮抗剂，对 5-HT2C（5-HT）受体的选择性约为 2000 倍。EMD-281,014 以前曾在临床上进行过测试，具有很高的转化潜力。在本研究中，我们评估了 EMD-281,014 对 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤的普通狨猴运动障碍和精神症状的影响。我们首先确定了 EMD-281,014 在狨猴中的药代动力学特征，然后在 MPTP 损伤的狨猴中给予导致临床相关血浆水平的剂量（0.01、0.03 和 0.1mg/kg）或载体，同时给予 L-3,4-二羟基苯丙氨酸（L-DOPA）。然后评估 EMD-281,014 对运动障碍、类精神病样行为（PLBs）和帕金森病的影响。当与 L-DOPA 联合使用时，与 L-DOPA/载体相比，EMD-281,014（0.03 和 0.1mg/kg）分别降低了 41.8%和 54.5%的峰值剂量运动障碍（P<0.05 和 P<0.001）。EMD-281,014（0.03 和 0.1mg/kg）还分别降低了 42.5%和 45.9%的峰值剂量 PLBs 的严重程度（P<0.05 和 P<0.001），与载体相比。EMD-281,014 对运动障碍和精神症状的抗作用是在不干扰 L-DOPA 抗帕金森病作用的情况下实现的。我们的结果表明，用 EMD-281,014 进行高度选择性 5-HT 受体阻断是一种有效缓解 PD 运动障碍和精神症状的方法，而不会对帕金森病残疾产生不利影响。
