| Project/Area Number |
06404055
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | Niigata University |
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Principal Investigator |
SHIMOJI Koki Niigata University School of Medicine Professor, 医学部, 教授 (30040158)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAKURA Tomohiro Niigata University Hospital Assistant, 医学部・附属病院, 助手 (80272847)
FUJIWARA Naoshi Niigata University Hospital Lecturer, 医学部・附属病院, 講師 (70181419)
FUKUDA Satoru Niigata University School of Medicine Associate Professor, 医学部, 助教授 (30116751)
KUMANISHI Toshiro Niigata University, Brain Research Institute Professor, 脳研究所, 助教授 (40018601)
森 寿 東京大学, 医学部, 助手 (00239617)
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| Project Period (FY) |
1994 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥34,500,000 (Direct Cost: ¥34,500,000)
Fiscal Year 1997: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1996: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 1995: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 1994: ¥22,100,000 (Direct Cost: ¥22,100,000)
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| Keywords | Anti-brain ischemia / Microinjury / Hippocampal slice / Intracellular Ca^<2+> / Receptor channel / NMDA receptor / Knock-out mice / 抗脳虚血機構 / MK-801 / ハロヘリドール / サブユニット / 虚血性神経細胞壊死 / 分子生物学 / AMPA受容体 / ペントバルビタール / 虚血性神経細胞死 / 卵母細胞 / NMDAリセプタサブユニット / ケタミン |
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| Research Abstract |
Survival rate following brain ischemia was significantly higher in previously brain-injured mice than in sham-operated mice, suggesting that certain protective factors against ischemia are intrinsically produced in the mechanically injured brain. To elucidate the mechanisms of intrinsic anti-ischemic activities, we projected the basic research from the standpoint of cell membrane and receptor channel mechanisms. The increase in intracellular Ca^<2+> concentrations induced by oxygen/glucose deprivation (ischemia in vitro) was inhibited in hippocampal slices from mice with prior mechanical microinjury at the hippocampal CAl region. The inhibition was remarkable in the areas close to the injury site. Mild acidosis inhibited the ischemia-induced rise in intracellular Ca^<2+> concentrations by attenuating both Ca^<2+> influx from the extracellular space and Ca^<2+> release from intracellular sites. The ischemia-induced rise in intracellular Ca^<2+> concentrations was followed by the increas
… More
e in extracellular glutamate concentrations, indicating that glutamate was released following the change in the permeability of cell membrane caused by the ischemia-induced rise in intracellular Ca^<2+> concentrations. Thus, the mechanisms of ischemic neuronal damage were likely to be heterogeneous. Furthermore, action mechanisms of drugs having anti-ischemic effects, such as dissociative anesthetics, MK-801, pentobarbital and butyrophenones, on the glutamate receptor channels were investigated by site-directed mutagenesis introduced into a certain subunits. These studies revealed that the second channel-forming segment of a certain subunit was crucial to constitute the block sites of anti-ischemic drugs on the glutamate receptor channel. The anesthetic effects of ketamine measured by loss of righting reflex in mice lacking the epsilon1 subunit of the NMDA receptor channel were weaker than the wild-type mice. Thus, anesthetic effects of ketamine may be mediated by the NMDA recetpor channel composed of the epsilon1 subunit. These research indicated the heterogeneity of anti-ischemic mechanisms and the involvement of a specific subunit molecule in anti-ischemic activities. Less
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