Frouni Imane, Kwan Cynthia, Bédard Dominique, Belliveau Sébastien, Bourgeois-Cayer Élodie, Gaudette Fleur, Beaudry Francis, Hamadjida Adjia, Huot Philippe
Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, BT 205, Montreal, QC, H3A 2B4, Canada.
Département de pharmacologie et physiologie, Université de Montréal, Montreal, QC, Canada.
Exp Brain Res. 2019 Jan;237(1):29-36. doi: 10.1007/s00221-018-5390-4. Epub 2018 Oct 8.
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective therapy for motor symptoms of Parkinson's disease (PD); however, with repeated administration, as many as 94% of PD patients develop complications such as L-DOPA-induced dyskinesia. We previously demonstrated that EMD-281,014, a highly selective serotonin 2A (5-HT) receptor antagonist, reduces the severity of dyskinesia in the parkinsonian marmoset, without interfering with L-DOPA anti-parkinsonian benefit. Here, we assessed the effects of EMD-281,014 on L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat. We first determined the pharmacokinetic profile of EMD-281,014, to administer doses leading to clinically relevant plasma levels in the behavioural experiments. Dyskinetic 6-OHDA-lesioned rats were then administered EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) or vehicle in combination with L-DOPA and AIMs severity was evaluated. We also assessed the effect of EMD-281,014 on L-DOPA anti-parkinsonian action with the cylinder test. We found that the addition of EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) to L-DOPA did not reduce AIMs severity (P > 0.05), when compared to vehicle. EMD-281,014 did not compromise L-DOPA anti-parkinsonian action. Our results suggest that the highly selective 5-HT receptor antagonist EMD-281,014 is well-tolerated by parkinsonian rats, but does not attenuate L-DOPA-induced AIMs. Our results highlight differences between rodent and primate models of PD when it comes to determining the anti-dyskinetic action of 5-HT receptor antagonists.
左旋3,4-二羟基苯丙氨酸（L-多巴）是治疗帕金森病（PD）运动症状最有效的药物；然而，反复给药后，多达94%的PD患者会出现诸如L-多巴诱导的运动障碍等并发症。我们之前证明，EMD-281,014，一种高选择性5-羟色胺2A（5-HT）受体拮抗剂，可减轻帕金森病狨猴的运动障碍严重程度，且不影响L-多巴的抗帕金森病疗效。在此，我们评估了EMD-281,014对6-羟基多巴胺（6-OHDA）损伤大鼠中L-多巴诱导的异常不自主运动（AIMs）的影响。我们首先确定了EMD-281,014的药代动力学特征，以便在行为实验中给予能达到临床相关血浆水平的剂量。然后给患有运动障碍的6-OHDA损伤大鼠给予EMD-281,014（0.01、0.03和0.1毫克/千克）或赋形剂，并联合L-多巴，评估AIMs的严重程度。我们还通过圆筒试验评估了EMD-281,014对L-多巴抗帕金森病作用的影响。我们发现，与赋形剂相比，在L-多巴中添加EMD-281,014（0.01、0.03和0.1毫克/千克）并没有降低AIMs的严重程度（P＞0.05）。EMD-281,014没有损害L-多巴的抗帕金森病作用。我们的结果表明，帕金森病大鼠对高选择性5-HT受体拮抗剂EMD-281,014耐受性良好，但不会减轻L-多巴诱导的AIMs。我们的结果突出了在确定5-HT受体拮抗剂的抗运动障碍作用方面，啮齿动物和灵长类PD模型之间的差异。
