2004 Fiscal Year Final Research Report Summary
Protective mechanisms of endogenous bioactive molecules on neuronal death associated with neurodegenerative disorders
| Project/Area Number |
14370780
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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 |
応用薬理学・医療系薬学
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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) |
2002 – 2004
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| Keywords | Neuronal death / Excitotoxicity / Reactive oxygen species / Neuroprotective factor / Nicotinic receptor / Serofendic acid / Nitric oxide / Glutamate |
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| Research Abstract |
We focused on endogenous low-molecular-weight substances as intrinsic protective mechanisms of the brain against glutamate-induced neuronal death. (1)Serofendic acid, a novel substance identified from fetal calf serum, markedly attenuated glutamate neurotoxicity. Serofendic acid inhibited NO donor-induced neuronal death, but did not affect glutamate receptor-mediated current responses. Serofendic acid also prevented generation of hydroxyl radical, and inhibited neuronal death induced by paraquat and hydrogen peroxide. Dimethylsulfoxide, a structural unit contained in serofendic acid, exhibited similar effects, but the effective concentrations of dimethylsulfoxide were about 3000 times as high as those of serofendic acid, suggesting that serofendic acid possesses neuroprotective actions independent of radical-scavenging activity. (2)We tested neuroprotective effects of several neurosteroids, as endogenous substances whose physicochemical properties resemble those of serofendic acid. Pregnenolone sulfate exacerbated, whereas pregnanolone sulfate inhibited, NMDA neurotoxicity. These effects were attributable to direct modulation of NMDA receptor channels by these compounds. (3)We examined neuroprotective activities of vitamin E analogs. Tocotrienols provided a significant protective effect against hydrogen-peroxide induced neuronal death, whereas α-tocopherol was without effect. Tocotrienols also inhibited induction of neuronal death by superoxide, NO as well as depletion of glutathione. Staurosporine-induced cell death was inhibited by α-tocotrienol. Several members of vitamin E analogs were shown to block apoptosis by mechanims independent of their antioxidant actions. (4)We found that acetylcholinesterase inhibitors including donepezil markedly inhibited glutamate neurotoxicity. The neuroprotective action emerged after prolonged treatment of neurons with donepezil for at least 24 h, and was mediated by stimulation of nicotinic acetylcholine receptors.
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[Journal Article] Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes α-synuclein inclusions.2004
Author(s)
Sawada H, Kohno R, Kihara T, Izumi Y, Sakka N, Ibi M, Nakanishi M, Nakamizo T, Yamakawa K, Shibasaki H, Yamamoto N, Akaike A, Inden M, Kitamura Y, Taniguchi T, Shimohama S.
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Journal Title
J.Biol.Chem. 279
Pages: 10710-10719
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons.2003
Author(s)
Nakamizo T, Kawamata J, Yoshida K, Kawai Y, Kanki R, Sawada H, Kihara T, Yamashita H, Shibasaki H, Akaike A, Shimohama S.
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Journal Title
J.Neurosci.Res. 71
Pages: 485-495
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Isolation of a diterpenoid substance with potent neuroprotective activity from fetal calf serum.2002
Author(s)
Kume T, Asai N, Nishikawa H, Mano N, Terauchi T, Taguchi R, Shirakawa H, Osakada F, Mori H, Asakawa N, Yonaga M, Nishizawa Y, Sugimoto H, Shimohama S, Katsuki H, Kaneko S, Akaike A.
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Journal Title
Proc.Natl.Acad.Sci.USA 99
Pages: 3288-3293
Description
「研究成果報告書概要(欧文)」より
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