| Project/Area Number |
07672470
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Sch.of Pharm.Sci., Univ.of Shizuoka |
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Principal Investigator |
YAMADA Shizuo Dept.of Biopharm., Sch.of Pharm.Sci., Univ.of Shizuoka, Associate Professor, 薬学部, 助教授 (80106434)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1996: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1995: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | Senescence-accelerated mouse / Deficits of learning and memory / Calcium antagonists / Nimodipine / Amlodipine / Calcium antagonist receptors / Brain pharmacokinetics / Calcium level / 学習・記憶障害 / 受動回避反応試験 |
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| Research Abstract |
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.
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