NMDA的拮抗特性是否与大鼠的抗帕金森样活性相关?金刚烷胺和美金刚胺的案例。

W Danysz, M Gossel, W Zajaczkowski, D Dill, G Quack
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引用次数: 71

摘要

对具有NMDA通道阻断特性的金刚烷胺(25、50、100 mg/kg)、美金刚胺(5、10、20 mg/kg)和MK-801(0.05、0.1、0.2 mg/kg)进行了氟哌啶醇诱导的猝倒、单胺缺失大鼠的运动活性和单侧黑质病变大鼠的旋转三种试验,以筛选大鼠抗帕金森药物。此外,评估了金刚烷胺和美金刚的血浆水平,以深入了解在行为活性剂量下达到的浓度范围。金刚烷胺和(+)-MK-801对氟哌啶醇诱导的猝厥产生剂量依赖的抑制作用,而美金刚仅在10 mg/kg剂量时产生明确的抗猝厥作用效果较差,但在20 mg/kg剂量时由于肌肉松弛活性而失效。所有药物对单胺衰竭大鼠的镇静作用均有减弱作用,金刚烷胺作用最小,MK-801最有效。在大鼠黑质损伤后诱导同侧旋转的效果也相同。根据目前的研究和已发表的数据,可以假设金刚烷胺、美金刚和MK-801在动物中显示抗帕金森样活性的剂量导致血浆水平导致NMDA拮抗。然而,在氟哌啶醇诱导的镇静试验中,金刚烷胺的效果高于美金刚,而旋转和利血平诱导的镇静效果则相反,这表明两种药物之间存在药效学差异。
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Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats?--case of amantadine and memantine.

Amantadine (25, 50, 100 mg/kg), memantine (5, 10, 20 mg/kg) and MK-801 (0.05, 0.1, 0.2 mg/kg), all having NMDA channel blocking properties, were compared in three tests used for screening of antiparkinsonian agents in rats, namely: haloperidol-induced catalepsy, locomotor activity in monoamine depleted rats and rotation in rats with a unilateral substantia nigra lesion. Additionally, plasma levels of amantadine and memantine were assessed to gain an insight into the concentration ranges achieved at behaviorally active doses. Amantadine and (+)-MK-801 produced dose-dependent inhibition of haloperidol-induced catalepsy while memantine was less efficacious producing clear-cut anticataleptic action at a dose of 10 mg/kg only but failing at 20 mg/kg due to myorelaxant activity. All agents attenuated sedation in monoamine depleted rats with amantadine being the least and MK-801 being the most effective. The same rank order of efficacy was seen in inducing ipsilateral rotations in rats after a substantia nigra lesion. On the basis of the present study and published data, it can be assumed that the doses of amantadine, memantine and MK-801 showing antiparkinsonian-like activity in animals result in plasma levels leading to NMDA antagonism. However, in the haloperidol-induced catalepsy test the efficacy of amantadine was higher than memantine, while the opposite was true for rotation and reserpine-induced sedation indicating pharmacodynamic differences between both agents.

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