Study of the antidyskinetic effect of eltoprazine in animal models of levodopa-induced dyskinesia
Study of the antidyskinetic effect of eltoprazine in animal models of levodopa-induced dyskinesia
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DOI：
10.1002/mds.25366
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发表时间：
2013-07-01
影响因子：
8.6
通讯作者：
Carta, Manolo
中科院分区：
文献类型：
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作者：
Bezard, Erwan;Tronci, Elisabetta;Carta, Manolo
近年来，5-羟色胺(5-羟色胺[5-HT])系统在L-3，4-二羟基苯丙氨酸(左旋多巴[L-多巴])诱导的帕金森病动物模型运动障碍的发生中起着重要作用。事实上，多巴胺作为一种错误的递质从5-羟色胺神经元释放出来，似乎有助于对多巴胺受体的搏动性刺激，导致异常不自主运动的出现。因此，能够抑制5-羟色胺神经元活性的药物有望用于运动障碍的治疗。在6-羟基多巴胺损毁大鼠和1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)处理的猕猴模型上，观察了混合5-HT1A/1B受体激动剂Etoprazine对L-多巴诱发的运动障碍的拮抗作用。这些数据表明，在实验模型中，埃托吡嗪对抑制运动障碍是极其有效的，尽管这种作用伴随着L-多巴治疗效果的部分恶化。有趣的是，人们发现埃托吡嗪(协同作用)增强了金刚烷胺的抗运动障碍作用。目前的数据表明，在临床前模型中，依托拉津对对抗运动障碍是非常有效的。然而，在给药后观察到的L-多巴效应的部分恶化是一个令人担忧的问题；这种副作用是由于动物模型的限制还是由于依托品的固有特性，需要在正在进行的临床试验中解决。提示小剂量依托品与金刚烷胺联合应用可能是增强抗运动障碍、减轻依托品所致的L-多巴疗效恶化的有效策略。(C)2013年运动无序社
The serotonin (5-hydroxytryptamine [5HT]) system has recently emerged as an important player in the appearance of l-3,4-dihydroxyphenylalanine (levodopa [l-dopa])-induced dyskinesia in animal models of Parkinson's disease. In fact, dopamine released as a false transmitter from serotonin neurons appears to contribute to the pulsatile stimulation of dopamine receptors, leading to the appearance of the abnormal involuntary movements. Thus, drugs able to dampen the activity of serotonin neurons hold promise for the treatment of dyskinesia. The authors investigated the ability of the mixed 5-HT 1A/1B receptor agonist eltoprazine to counteract l-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned rats and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. The data demonstrated that eltoprazine is extremely effective in suppressing dyskinesia in experimental models, although this effect was accompanied by a partial worsening of the therapeutic effect of l-dopa. Interestingly, eltoprazine was found to (synergistically) potentiate the antidyskinetic effect of amantadine. The current data indicated that eltoprazine is highly effective in counteracting dyskinesia in preclinical models. However, the partial worsening of the l-dopa effect observed after eltoprazine administration represents a concern; whether this side effect is due to a limitation of the animal models or to an intrinsic property of eltoprazine needs to be addressed in ongoing clinical trials. The data also suggest that the combination of low doses of eltoprazine with amantadine may represent a valid strategy to increase the antidyskinetic effect and reduce the eltoprazine-induced worsening of l-dopa therapeutic effects. (c) 2013 Movement Disorder Society