| Project/Area Number |
17310124
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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 |
Living organism molecular science
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| Research Institution | Gifu University |
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Principal Investigator |
FURUTA Kyoji Gifu University, Graduate School of Medicine, Associate Professor (40173538)
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| Co-Investigator(Kenkyū-buntansha) |
HIRATA Yoko Gifu University, Factclty of Engineering, Associate Professor (50271523)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥13,400,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥900,000)
Fiscal Year 2007: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2006: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥5,700,000 (Direct Cost: ¥5,700,000)
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| Keywords | Neuroprotective / Cyclopentenone / Parkinson's disease / Apoptosis / Prostaglandin / Keapl / Molecular Probe / 抗アポトーシス / スルファニル置換体 / NEPP |
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| Research Abstract |
In this study, we investigated the design, synthesis and biological activities of novel neuroprotactive cyclopentenone prostaglandin analogs.
1. A variety of the analogs of NEPP, artificial cyclopentenone prostaglandins exerting neuropnatective activities, were synthesized and the structure-activity relationship studies of the(=pounds for suppression of manganese-induced apoptosis of PC12 cells were carried out Results showed that a cross-conjugated dienone moiety and a modestly lipophilic ω-side chain are escrintial for the suppression of apoptosis Topological modification of the five-membered ring moiety succeeded in elaborating novel derivatives with improved anti-apoptotic effects and reduced cytotoxicity The compounds are promising candidates for further development as agents against neurodegenerative diseases such as Parkinson's disease.
2. Biochemical analysis using NEPP probes revealed that the neuroprotective effect of NEPP against oxidative stress is ascribed to the induction o
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f HO-1, a stress-responsive protein, at both protein and mRNA levels. Further analysis utilizing a biotinylated probe of NEPP demonstrated that Keapl is the cellular target molecule of NEPP. Keapl is a negative regulator of the antioxidant transcription factor Nr12 that involved in the HO-1 induction. Preferential accumulation of NEPP in neurons was also proven by tissue staining with the biotinylated probe.
3. Novel analogs of NEPP with modified five-membered ring were synthesized to assay their anti-apoptotic effects in manganese-induced apoptosis of PC12 cells. The compounds with a phenylthio substituent at the alpha-position of the carbonyl group exerted increased anti-apoptotic activity compared with NEPP. Several derivatives with substituents on the phenylthio group were synthesized for structure-activity relationship study. This analysis identified a p-amino derivative as the most potent and least toxic compound. Moreover, analysis of intracellular signaling pathways disclosed that unlike NEPP, which inhibits the activation of JNK by MKK4, the phenylthio derivative targets the signal molecule between the phosphorylation of c-Jun and the activation of caspase-9. Less
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