| Project/Area Number |
11470283
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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 |
Cerebral neurosurgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KIRINO Takaaki The University Hospital, Neurosurgery, Professor, 医学部・附属病院, 教授 (90126045)
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| Co-Investigator(Kenkyū-buntansha) |
NOBUTAKA Kawahara The University Hospital, Neurosurgery, Assistant Professor, 医学部・附属病院, 講師 (60214673)
川合 謙介 東京大学, 医学部・附属病院, 助手 (70260924)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2000: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1999: ¥9,200,000 (Direct Cost: ¥9,200,000)
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| Keywords | cerebral ischemia / glutamate transporter / knockout mice / gerbil / delayed neuronal death / GLT-1 |
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| Research Abstract |
Elucidation of the Mechanisms for Glutamate Release in Ischemic Neuronal Injury
There have been an accumulating evidence that extracellular glutamate is contineously taken up and regulated in concentration by glutamate transporters. Especially, GLT-1 is specifically and widely distributed in forebrain area. Recently, GLT-1 has reported to release intracellular glutamate toward extracellular space in a condition such as ischemia.
To test this hypothesis and make sure the function of GLT-1 during ischemia, we determined extracellular glutamate concentration in gerbils with naive and ischemic condition by inhibition of glutamate transporter. In addition, we produced a focal cerebral ischemia by cauterization of the middle cerebral artery in mice with GLT-1 gene deleted and its wild type.
Results :
(1) We infused tPDC, an inhibitor of a glutamate transporter and collected extracellular fluid of gerbil brain by a microdialysis method. We confirmed that extracellular glutamate increased during an inhibition of a glutamate transporter. This result indicates that a glutamate transporter plays an important role in regulating extracellular glutamate concentration. As the next step, we induced a transient global ischemia to gerbils which were pre-infused with tPDC.We could not confirm the significant protective effect against neurons in CA1 sector of the hippocampus of the animals.
(2) We used GLT-1 gene knockout mice to examine whether ischemic neuronal death is accelerated and an infarct size is augmented. By producing a permanent focal cerebral ischemia, there was no differences in infarct volumes (homozygotes : 12.6±10.3, wild type : 12.6±6.8, Mean±SD mm^3). Since there is a possibility that the severity of an initial ischemic insult but not glutamate toxicity affected the neuronal cell death, we are ongoing to measure the infarct volumes by adopting ischemia-reperfusion models which are less severe than permanent ischemia.
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