| Project/Area Number |
13672329
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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 |
医薬分子機能学
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| Research Institution | St Marianna University, School of Medicine |
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Principal Investigator |
IGARASHI Rie Institute of Medical Science, Frontier Medicine Development, Senior Associate Professor, 難病治療研究センター, 助教授 (80202860)
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| Co-Investigator(Kenkyū-buntansha) |
TAKENAGA Mitsuko Institute of Medical Science, Frontier Medicine Development, Assistant Professor, 難病治療研究センター, 講師 (10236490)
中山 利明 旭硝子株式会社, 中央研究所, 研究員
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | Brain derived neurotrophic factor (BDNF) / lecithin / cellular affinity / MAP kinase (ERK1 / 2) / db / db mice / p38 / 修飾ペプチド / 食欲中枢 / db / dbマウス |
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| Research Abstract |
We synthesized lecithinized brain-derived neurotrophic factor (lecithinized-BDNF), in which several molecules of a lecithin derivative were bound to recombinant human BDNF. We evaluated its pharmacological activity in C57BL/KsJ-db/db mice, and assessed its targetability and affinity for the nervous system. When administered subcutaneously, lecithinized-BDNF markedly reduced the plasma glucose level, food intake, and body weight in C57BL/KsJ-db/db diabetic mice. Its potency was over 20 times greater than that of unmodified BDNF. We studied the mechanism of marked enhancement of pharmacological activity. In vitro cell growth activity of lecithinized-BDNF using MTT assay was lower than unmodified BDNF, steric hindrance of lecithine moieties. Moreover, the plasma BDNF level after subcutaneous administration of lecithinized-BDNF was not higher, compared with unmodified BDNF. The accumulated lecithinized-BDNF in the cerebrum, cerebellum, and spinal cord were higher than that of unmodified BDNF. We found finally that in vitro binding of lecithinized-BDNF for PC-pAB1 neural cells was much higher than that of unmodified BDNF. Moreover, lecithinized-BDNF bound to PC-pAB1 cells didn't change with even excess unmodified BDNF or even excess lecithinized-BDNF. PC-pAB1 cells treated with lecithinized-BDNF showed a sustained MAP kinase (ERK1/2) activation. These data would indicate that the high affinity of lecithinized-BDNF for the target cells followed by prolonged MAPK activation would play an important role on its more potent pharmacological activity.
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