Development of neuroprotective drugs that modulate glutamate transporters.
| Project/Area Number |
10470508
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | THE UNIVERSITY OF TOKYO |
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Principal Investigator |
MATSUKI Norio The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (70126168)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Glutamate Transporter / Glial Cells / Astrocyte / Endothelin / Amyloid β / 神経栄養因子 / 神経保護 |
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| Research Abstract |
Glutamate is the major excitatory neurotransmitter of the mammalian central nervous system, but also one of neurotoxic substances. Generally extracellular glutamate level is kept low by NaィイD1+ィエD1-dependent transports into glial and neuronal cells. Molecular cloning led to the isolation of cDNAs for three glutamate transporter subtypes in nonhuman as well as human systems. However, little is known about modulatory factors for the transport systems. Effects of trophic factors on glutamate uptake were investigated in cultured cortical astrocytes. Basic fibroblast growth factor (bFGF) enhanced the glutamate uptake in a concentration-dependent manner. Insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) also augmented glutamate uptake significantly. But neither PDGF nor HGF affected the transport. Western blot analysis revealed that GLAST, but not GLT-1, protein level is augmented in astrocytes treated with trophic factors. These results suggest that trophic factors increase the expression of GLAST and consequently enhance the glutamate uptake. Moreover, pharmacological studies show that these trophic factors' regulations require the activation of ras-MAP kinase cascade and PI3 kinase. These studies may be useful in understanding the regulation of expression and/or function of glial glutamate transporters.
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Report
(3 results)
Research Products
(2 results)
