| Project/Area Number |
17390157
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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 |
Applied pharmacology
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| Research Institution | Kyoto University |
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Principal Investigator |
AKAIKE Akinori Kyoto University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (80135558)
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| Co-Investigator(Kenkyū-buntansha) |
KATSUKI Hiroshi Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (40240733)
KUME Toshiaki Kyoto University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 薬学研究科, 助手 (10303843)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 2006: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2005: ¥9,600,000 (Direct Cost: ¥9,600,000)
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| Keywords | Neuronal death / Excitotoxicity / Nitric oxide / Serofendic acid / Donepezil / Nicotinic receptor |
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| Research Abstract |
We focused on the low-molecular-weight substances that controlled the neuronal death induced by glutamate and radical stress. 1, Serofendic acid, a low-molecular-weight substance of atisane-type diterpenoids derived from fetal calf serum, prevents glutamate-induced apoptosis in cultured cortical neurons by the prevention of loss of mitochondrial membrane potential and the reduction of the process of caspase-3 activation. 2, We investigated the effect of serofendic acid on ischemic injury induced by a transient occlusion of the middle cerebral artery in rats. Serofendic acid significantly reduced total infarct volume, similar to edaravone, a free radical scavenger. These results suggest that intracerebroventricular administration of serofendic acid prevents the neurodegeneration induced by a transient focal cerebral ischemia and reperfusion. 3, We found that donepezil and galanthamine prevented glutamate neurotoxicity through α4-and α7-nAChRs, followed by the PI3K-Akt pathway, and that
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tacrine protected neuronal cells through a different pathway. 4, We examined the mechanisms of thrombin cytotoxicity in the striatum in vivo. Thrombin induced neuronal death and microglial activation around the injection site. Neuronal loss without any sign of nuclear fragmentation was observed. Thrombin-induced damage was partially but significantly reduced by concomitant administration of inhibitors of MAPK pathways. Thus, MAPK pathways and microglial activation may serve as therapeutic targets of pathogenic conditions associated with hemorrhagic stroke. 5, We examined the role of endogenous agonists at the glycine site of NMDA receptors in excitotoxic retinal damage in vivo. Endogenous D-serine is at least in part involved in pathological processes mediated by NMDA receptor over-activation in the retina. The levels of endogenous glycine site agonists influence the severity of NMDA receptor-mediated excitotoxic retinal damage in vivo. Both glycine and D-serine contribute to the excitotoxic processes in the retina. Less
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