ARE NMDA ANTAGONISTIC PROPERTIES RELEVANT FOR ANTIPARKINSONIAN-LIKE ACTIVITY IN RATS - CASE OF AMANTADINE AND MEMANTINE
ARE NMDA ANTAGONISTIC PROPERTIES RELEVANT FOR ANTIPARKINSONIAN-LIKE ACTIVITY IN RATS - CASE OF AMANTADINE AND MEMANTINE
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DOI：
10.1007/bf02253435
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发表时间：
1994-01-01
期刊：
影响因子：
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通讯作者：
QUACK, G
中科院分区：
文献类型：
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作者：
DANYSZ, W;GOSSEL, M;QUACK, G
金刚烷胺（25、50、100mg/kg）、美金刚（5、10、20mg/kg）和 MK-801（0.05、0.1、0.2mg/kg）均具有 NMDA 通道阻断特性，在用于筛选大鼠抗帕金森病药物的三项测试中进行比较，即：氟哌啶醇诱导的僵直症、单胺耗竭大鼠的运动活动和旋转在具有单侧黑质病变的大鼠中。此外，还评估了金刚烷胺和美金刚的血浆水平，以深入了解行为活跃剂量下达到的浓度范围。金刚烷胺和 (+)-MK-801 对氟哌啶醇诱发的强直性昏厥产生剂量依赖性抑制作用，而美金刚则不太有效，仅在 10 mg/kg 剂量下产生明确的抗强直作用，但由于肌肉松弛活性，在 20mg/kg 剂量下则失效。所有药物均减弱单胺耗尽大鼠的镇静作用，其中金刚烷胺效果最弱，MK-801 最有效。在黑质损伤后诱导大鼠同侧旋转时观察到相同的功效排序。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 在动物体内显示出抗帕金森病样活性的剂量会导致血浆水平产生 NMDA 拮抗作用。然而，在氟哌啶醇诱发的强直性昏厥试验中，金刚烷胺的疗效高于美金刚，而旋转和利血平诱发的镇静则相反，表明两种药物之间的药效学差异。
Amantadine (25, 50, 100mg/kg), memantine (5, 10, 20mg/kg) and MK-801 (0.05, 0.1, 0.2mg/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 assesssed 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 20mg/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.