Studies of molecular mechanisms of rotenone-induced apoptosis and neurotrophic substances for dopaminergic neurons
| Project/Area Number |
16500240
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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 Gifu University, Faculty of Engineering, Associate Professor, 工学部, 助教授 (50271523)
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| Co-Investigator(Kenkyū-buntansha) |
FURUTA Kyoji Gifu University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (40173538)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | apoptosis / rotenone / manganese / Parkinson's disease / caspase-3 / prostaglandin / ドーバミン神経 / 神経保護物質 / ドーパミン / 活性酸素種 |
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| Research Abstract |
Both rotenone and manganese are possible neurotoxins for a wide variety of cell and neuronal types including dopaminergic neurons and induce apoptosis in various cells. In this study, we focused on the mechanism of rotenone as toxins. Rotenone induced apoptosis via enhancing the amount of mitochondrial ROS production whereas it has little effect on the activation of JNK and p38 MAPK pathways in PC12 cells. Nerve growth factor suppressed rotenone-induced apoptosis through the activation of the PI 3-kinase pathway not MAP kinase pathway. Neurite outgrowth-promoting prostaglandins (NEPPs), cyclopentenone prostaglandin derivatives including NEPP6 and NEPP11, are found to be neurotrophic. They promote neurite outgrowth of PC12 cells and dorsal root ganglia explants in the presence of nerve growth factor, and prevent neuronal cell death of HT22 cells and cortical neurons induced by various stimuli. However, these are also toxic at relatively high concentrations. In this study, a highly sensi
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tive assay of caspase-3/7 was used for screening chemically synthesized NEPP derivatives. Several compounds (GIF-0642, GIF-0643, GIFU-0644, GIF-0745, GIF-0747) out of 44 derivatives inhibited manganese-induced activation of caspase-3/7 in PC12 cells. In addition, Western blotting showed that GIF-0642 and GIF-0747 inhibited manganese-induced caspase-9 activation. GIF-0642 and GIF-0747 also completely inhibited manganese-induced DNA fragmentation in PC12 cells. These results suggest that the compounds prevent manganese-induced apoptosis. Furthermore, NEPP derivatives suppressed glutamate-induced caspase-3/7 activation in HT22 hippocampal cell line. Effective NEPP derivatives have phenylsulfanyl group as a common structure. The results indicate that the phenylsulfanyl group plays an important role in anti-apoptotic effect of NEPP derivatives. Further efforts to modify the structure of cyclopentenone prostaglandin derivatives that strengthen the inhibitory action on neurotoxin-induced apoptosis and eliminate cytotoxicity may provide neurotrophic small molecules that are helpful in preventing neurodegenerative disorders such as Parkinson's disease. Less
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Report
(3 results)
Research Products
(5 results)
