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Brain pharmacokinetics and receptor binding characcteristics of calcium antagonists for improvement of brain dysfunction

钙拮抗剂改善脑功能障碍的脑药代动力学和受体结合特性

基本信息

批准号：
07672470
负责人：
YAMADA Shizuo
金额：
$ 1.54万
依托单位：
Sch.of Pharm.Sci., Univ.of Shizuoka
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Characteristics of L-type calcium (Ca^<++>) antagonist receptors in brains of senescence-accelerated prone mice (SAMP8) showing age-related deterioration of learning and memory were examined using (+)-[^3H] PN 200-110 as a radioligand. There was a significant decrease in maximal number of binding sites (Bmax) for (+)-[^3H] PN 200-110 in brains of SAMP8 compared to the control mice (SAMR1) both in vitro and in vivo. Following intravenous injection of (+)-[^3H] PN 200-110, the area under the curve for brain concentration of the radioligand (AUC_<brain>) in SAMP8 was significantly smaller than that in SAMR1. These data suggest a decrease in the density of Ca^<++> antagonist receptors in brain of SAMP8. Chronic oral administration of nimodipine and nicardipine to SAMP8 caused a significant increase in Bmax values of (+)-[^3H] PN 200-110 binding in the cerebral cortex and hippocampus. This may reflect up-regulation of brain Ca^<++> antagonist receptors as a result of the prolonged blockade by nimodipine and nicardipine. On the other hand, similar administration of amlodipine failed to produce enhancement of Bmax values of (+)-[^3H] PN 200-110 binding. The brain concentration of [^3H] nimodipine after intravenous injection of the radioligand in mice and its ratio to plasma concentration were significantly higher than those of (-)-[^3H] amlodipine. Also, a significant amount of specific binding in brain of these mice was detected in vivo with [^3H] nimodipine but not with (-)-[^3H] amlodipine. Thus, the present study provides pharmacokinetic and pharmacodynamic evidence for the utility of nimodipine against neurological disorders associated with the aging brain.

以(+)-[~(3 H)]PN200-110为放射性配基，研究了衰老加速易感小鼠脑内L钙拮抗剂受体的特性。在体内外，SAMP8组小鼠脑内(+)-[~(3 H)]PN 200-110的最大结合位点数(Bmax)均显著低于对照组(SAMR1)。静脉注射(+)-PN200-110后，SAMP8的放射性配基脑内浓度曲线下面积明显小于SAMR1。这些数据表明SAMP8大鼠脑内钙拮抗剂受体密度降低。慢性经口给予尼莫地平和尼卡地平可引起大脑皮层和海马区(+)-[~(3 H)]PN200-110结合的Bmax显著增加。这可能反映了由于尼莫地平和尼卡地平的长期阻断，脑内钙拮抗剂受体的上调。同样剂量的氨氯地平不能增强(+)-[^~3H]pN 200-110结合的Bmax。小鼠静脉注射放射性配基后，尼莫地平的脑内浓度及其与血药浓度的比值显著高于(-)-氨氯地平。在小鼠脑内，尼莫地平有显著的特异性结合，而(-)-氨氯地平则没有。因此，本研究为尼莫地平治疗与脑老化相关的神经疾病提供了药代动力学和药效学证据。