2001 Fiscal Year Final Research Report Summary
Roles of endothelin receptors in astrocytic activation on brain pathologies
| Project/Area Number |
12670086
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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 | Osaka University |
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Principal Investigator |
KOYAMA Yutaka Osaka Univ., Grad. Sch. Of Pharmaceutical Sci., Associate Prof., 薬学研究科, 助教授 (00215435)
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| Co-Investigator(Kenkyū-buntansha) |
BABA Akemichi Osaka Univ., Grad. Sch. Of Pharmaceutical Sci., Prof., 薬学研究科, 教授 (70107100)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Endothelin / Astrocyte / Brain injury / Neurotrophic drug / focal adhesion kinase / neurotrophic factors |
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| Research Abstract |
1. Endothelin-induced production of neurotrophic factors : Endothelin (ET) stimulated production of GDNF and BDNF, well-known neurotrophic factors, in rat cultured astorcytes. ET-induced GDNF production was inhibited by removal of intracellular Ca^<2+> and inhibition of ERK signal pathway. An inhibitor of NFkB (pyrrolidin dithiocarbamate) and pre-treatment with glucocorticoid had no effect on the ET-induced GDNF production, while GDNF production induced by H_2O_2 was prevented by them. Continuousinfusion of ETs into cerebral ventricle for 7 days increased GDNF and BDNF in hippocampus and striatum, respectively. Immunohistechemical examinations showed that these neurotrophic factors were produced by astrocytes. These findings suggest that activation of astrocytic ET receptors can be one target of neurotrophic drugs to stimulate neurotrophic factors.
2. Endothelin-induced astrocytic proliferation : The mechanisms of ET-indeuced astrocytic proliferation by focusing roles of focal adhesion kinase (FAK), a tyrosine kinase associated with focal adhesions. ET stimulated phosphorylation of both FAK and ERK in astrocytes. Cytochalasin D inhibited ET-induced phosphorylation of FAK, but not that of ERK. Cytochalasin D reduced the incorporation of bromdeoxyuridine (BrdU) induced by ET-1. A transient transfection with wild-type FAK was followed byan increase in astrocytic BrdU incorporation. The effect of ET-1 on BrdU incorporation was diminished in astrocytes transfected with dominant-negative FAK mutants. ET-1 increased expression of cyclin D1 and D3 proteins in cultured astrocytes. Transfection with wild-type FAK increased expression of cyclin D3 in astrocytes, while that of cyclin D1 was not affected. The ET-induced increase in cyclin D3 expression, but not D1, was prevented by dominant-negative FAK mutants. These results suggest an involvement of FAK in astrocytic proliferation induced by ETs.
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Research Products
(24 results)
