Development of endothelin antagonists protecting against ischemic neuronal degeneration
| Project/Area Number |
07672463
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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 | Faculty of Medicine, Kyushu University |
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Principal Investigator |
KATAOKA Yasufumi Kyushu University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (70136513)
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| Co-Investigator(Kenkyū-buntansha) |
NIWA Masami Nagasaki University, Faculty of Medicine, Professor, 医学部, 教授 (20136641)
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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 |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1996: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1995: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Endothelin / Endothelin receptors / Endothelin antagonists / brain ischemia / brain damage / striatum / dopamine / nitric oxide |
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| Research Abstract |
The present study was aimed at elucidating a neuroprotective action of endothelin (ET) antagonists on ischemic neuronal degeneration with the in vitro and in vivo rat model for brain ischemia. (1) RES-701-1 (ETB antagonist) but not BQ-123 (ETA antagonist) inhibited the release of dopamine from rat striatal slices. (2) Striatal response to the test stimulation remained impaired up to 2 hr after the pulse exposure of ET-1 under conditions of hypoglycemia/hypoxia. We termed this event striatal dopaminergic dysfunction'. RES-701-1 but not BQ-123 led to a recovery from this striatal dysfunction. An inhibitor of nitric oxide synthase closely associated with ETB function improved ET-1 neurotoxicity. (3) The delayd neuronal death occurred in the hippocampus CA1 pyramidal cell layr of rats at 7 days after a 20-min bilateral carotid occlusion according to Pulsinelli's method. RES-701-1 and T-0201 (ETA/ETB antagonist) injected into the lateral ventricle 10 min after reperfusion protected against ischemic neuronal death. (4) The quantitative receptor autoradiographic method we used revealed a dramatic increase in 125-I-ET-1 binding sites in the hippocampus CA1 pyramidal cell layr with neuronal death. The de novo 125-I-ET-1 binding sites were characteristically the ETB receptor.
The present findings provide evidence that ETB antagonists could be operative for the treatment of ischemic brain damage.
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Report
(3 results)
Research Products
(10 results)
