| Project/Area Number |
13670090
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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 |
General pharmacology
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| Research Institution | NAGASAKI UNIVERSITY |
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Principal Investigator |
SAKURAI Yasuko NAGASAKI UNIVERSITY, GRADUATE SCHOOL OF BIOMEDICAL SCIENCE, INSTRUCTOR, 大学院・医歯薬学総合研究科, 講師 (80291532)
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| Co-Investigator(Kenkyū-buntansha) |
YAMASHITA Kimihiro NAGASAKI UNIVERSITY, SCHOOL OF ENVIRONMENTAL SCIENCES, ASSOCIATE PROFESSOR, 環境科学部, 助教授 (50192399)
NIWA Masami NAGASAKI UNIVERSITY, GRADUATE SCHOOL OF BIOMEDICAL SCIENCE, PROFESSOR, 大学院・医歯薬学総合研究科, 教授 (20136641)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | ISCHEMIA-RELATED NEURONAL DEATH / MICROGLIA / ASTROCYTES / MCP-1 / ET_B RECEPTOR / BLOOD BRAIN BARRIER |
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| Research Abstract |
We have studied the mechanism of ischemia-related neuronal death leading to dementia. Our previous results demonstrated that microglia expressing endothelin ETB (ETB) receptor aggregated in the pyramidal layer of the hippocampus where the selective neuronal death occurred. We tried to induce ischemia in the spotting lethal (sl) rats with lack of the ETB gene expression. As the rats homozygous for this mutation die shortly due to the congenital distal aganglionosis, they were legated an unilateral carotid artery and exposed to hypoxia at 2 weeks old according to the neonatal ischemia model. The ipsilateral pyramidal cells were lost in both ETB^<+/+> and ETB^<sl/sl> and the process was different from that in SHRSP because of the clear histochemical damage at 24h after reperfusion in the neonatal model. Then we investigated the expression of monocyte chemoattractant protein-1 (MCP-1) because our previous study showed the increased permeability of blood brain barrier (BBB) at 24h after the ischemia-reperfusion in SHRSP. MCP-1 mRNA was expressed in the astrocytes of dentate gyrus at 24h after 10 min-ischemia and distributed in the CA1 subfield at 48h. The expressing cells at 48h in the CA1 subfield was almost astrocytes. Increased MCP-1 protein concentration was also demonstrated in the hippocampus at 48h by ELISA. Cultured astrocytes were used to clarify the induction of MCP-1 after the in vitro ischemic condition, aglycemia/hypoxia by astrocytes themselves. Expression of MCP-1 mRNA was dramatically increased in the astrocytes from SHRSP, however a little in those from WKY, normotensive rats. These results suggest that MCP-1 expressed in astrocytes after the ischemia-reperfusion might make monocytes migrate into the brain and also activate microglia. The substances to inhibit the secretion or function of MCP-1 could inhibit the delayed neuronal death induced by a transient global ischemia in SHRSP.
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