Noradrenoceptor antagonism with idazoxan improves L-dopa-induced dyskinesias in MPTP monkeys
Noradrenoceptor antagonism with idazoxan improves L-dopa-induced dyskinesias in MPTP monkeys
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DOI：
10.1007/s002109900167
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发表时间：
2000-02-01
影响因子：
3.6
通讯作者：
Bédard, PJ
中科院分区：
文献类型：
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作者：
Grondin, R;Tahar, AH;Bédard, PJ
用左旋多巴治疗帕金森病在大多数患者中受到运动障碍的困扰。去甲肾上腺素/多巴胺的相互作用提出了行为，生物化学，生理和解剖学的理由。本研究的目的是在帕金森氏病灵长类动物模型中测试α（2）-肾上腺素受体拮抗剂咪唑克生的潜在抗运动障碍作用。使用了6只雌性食蟹猴，这些猴先前因毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）而患帕金森病，并在数月内表现出症状不变。所有人对左旋多巴都有反应，但都出现了运动障碍，这在每次给药时都有表现。在研究的第一部分中，将7个剂量的咪唑克生（范围从0.25 mg/kg至10 mg/kg，p.o.）与载体一起或与固定剂量的L-多巴/苄丝肼（100/25 mg，p.o.）组合施用。在研究的第二部分，每天给予固定剂量的咪唑克生（7.5 mg/kg），持续10天，并在第1、4、7和10天将左旋多巴加入咪唑克生中。溶剂（空胶囊）用作对照。咪唑克生本身（范围为5 mg/kg至10 mg/kg）增加了运动活性，并改善了3只动物的残疾评分，几乎没有运动障碍。在与左旋多巴的组合中，咪唑克生没有损害抗帕金森病反应，但在7.5 mg/kg和10 mg/kg的剂量下，所有6只动物中的运动障碍显著减少高达65%，并延迟其发作，因此延长了无运动障碍的“ON”状态。重复给药10天后，咪唑克生的抗运动障碍作用仍得以维持。在第10天，运动反应L-多巴显着增强的长期管理的咪唑克生。我们的研究结果表明，咪唑克生有一定的抗帕金森病的效果，它本身可能构成一个有用的辅助左旋多巴，因为它可以减少运动障碍，而不损害症状的缓解，这种效果随着时间的推移保持在这个模型中。
Treatment of Parkinson's disease with L-dopa is plagued in a majority of patients by dyskinesias. Noradrenaline/dopamine interactions are proposed on behavioral, biochemical, physiological and anatomical grounds. The aim of the study was to test the potential antidyskinetic effect of the alpha(2)-adrenoceptor antagonist, idazoxan, in a primate model of Parkinson's disease. Six female cynomolgus monkeys previously rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and presenting an unchanged syndrome for several months were used. All responded readily to L-dopa but had developed dyskinesias which were manifested with each dose. In the first part of the study, seven doses of idazoxan (ranging from 0.25 mg/kg to 10 mg/kg, p.o.) were administered together with the vehicle or in combination with a fixed dose of L-dopa/benserazide (100/25 mg, p.o.). In the second part of the study, a fixed dose of idazoxan (7.5 mg/kg) was administered daily for 10 days and L-dopa was added to idazoxan on days 1, 4, 7 and 10. Vehicle (empty capsule) was used as control. Idazoxan, by itself (ranging from 5 mg/kg to 10 mg/kg), increased locomotor activity and improved the disability score with virtually no dyskinesias in three animals. In combination with L-dopa, idazoxan did not impair the antiparkinsonian response but significantly reduced dyskinesias in all six animals up to 65% at doses of 7.5 mg/kg and 10 mg/kg and delayed their onset, so that the "ON" state without dyskinesias was prolonged. The antidyskinetic effect of idazoxan was maintained when repeatedly administered for 10 days. On day 10, the locomotor response to L-dopa was significantly potentiated by chronic administration of idazoxan. Our results indicate that idazoxan has some antiparkinsonian effect of its own and may constitute a useful adjunct to L-dopa as it can reduce dyskinesias without impairing the relief of symptoms, this effect being maintained over time in this model.