2011 Fiscal Year Final Research Report
Up-regulation of glial cell line-derived neurotrophic factor by newly synthesized cyclopentenone derivatives : Studies on cellular mechanisms in vitro and effectiveness in vivo
| Project/Area Number |
21500348
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Gifu University |
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Principal Investigator |
HIRATA Yoko 岐阜大学, 工学部, 准教授 (50271523)
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| Co-Investigator(Renkei-kenkyūsha) |
FURUTA Kyoji 岐阜大学, 医学研究科, 准教授 (40173538)
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| Project Period (FY) |
2009 – 2011
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| Keywords | グリア細胞株由来神経栄養因子 / 脳由来神経栄養因子 / 神経成長因子 / C6グリオーマ細胞 |
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| Research Abstract |
Newly synthesized(arylthio) cyclopentenone derivatives(GIF-0642, GIF-0643) suppressed manganese-induced apoptosis in PC12 cells by inhibiting caspase activation and cytochrome c release from mitochondria. GIF-0642 and GIF-0643 were also neuroprotective against oxidative stress-induced cell death in mouse hippocampal HT22 cells and C6 glioma cells. GIF-0642 and GIF-0643 bound to peroxisome proliferator-activated receptor-γ(PPARγ) and activated PPARγ-RXR heterodimers. Furthermore, these compounds induced gene expression of GDNF, BDNF and nerve growth factor(NGF) in C6 glioma cells. GIF-0642 and GIF-0643 stimulated phosphorylation of various signaling molecules in the MAP kinase pathway. We synthesized biotinylated(arylthio) cyclopentenones to study direct interaction between various signaling molecules in the MAP kinase pathway and chemical compounds using a pull-down assay. The results suggest that(arylthio) cyclopentenones directly bind to Raf molecule. On the other hand, intraperitoneal administration of GIF-0642 in mice failed to stimulate neurotrophic factors such as GDNF, BDNF, and NGF in the brain. Further study is required to determine the effects of(arylthio) cyclopentenones on the expression of neurotrophic factors in vivo. These include dosage of chemical compounds, solvents for dissolving chemical compounds to use, and the method of administration.
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