2006 Fiscal Year Final Research Report Summary
A direct correlation between ischemic injury and extracellular glycine concentration in mice with genetically altered activities of the glycine cleavage multi-enzyme system
| Project/Area Number |
17591497
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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 |
Cerebral neurosurgery
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| Research Institution | University of Yamanashi |
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Principal Investigator |
KINOUCHI Hiroyuki University of Yamanashi, Department of Research Interdisciplinary Graduate school of Medicine and Engineering, Professor, 大学院医学工学総合研究部, 教授 (30241623)
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| Co-Investigator(Kenkyū-buntansha) |
SUGAWARA Taku Akita University, School of Medicine, Assistant Professor, 医学部, 講師 (80241660)
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| Project Period (FY) |
2005 – 2006
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| Keywords | cerebral ischemia / NMDA / apoptosis / glycine / transgenic / knock out / マイクロダイアリーシス / NMDA |
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| Research Abstract |
[Background and Purpose] Ischemia elicits rapid release of various amino acid neurotransmitters. Glutamate surge activates N-methyl-D-aspartate (NMDA) glutamate receptors, triggering deleterious process of neurons. Although glycine is a coagonist of the NMDA receptor, the effect of extracellular glycine concentration on ischemic injury remains controversial. To approach this issue we examined ischemic injury in mice with genetically altered activities of the glycine cleavage multi-enzyme system (GCS), which plays a fundamental role in maintaining extracellular glycine concentration. [Materials and Methods] A mouse line with increased GCS activity (340% of C57BL/6 control mice) was generated by transgenic expression of glycine decarboxylase, a key GCS component (high-GCS mice). Another mouse line with reduced GCS activity (29% of controls) was established by transgenic expression of a dominant negative mutant of glycine decarboxylase (low-GCS mice). We examined the neuronal injury after transient occlusion of middle cerebral artery in these mice, measuring extracellular aminoacid concentrations by microdialysis method. [Results] The high-GCS and low-GCS mice had significantly lower and higher basal concentrations of extracellular glycine than controls, respectively. In low-GCS mice, extracellular glycine reached to 2-hold control level during ischemia and the infarction volume was significantly increased by 69% of controls. In contrast, high-GCS mice had significantly smaller infarction volume by 21%. No significant difference was observed in extracellular glutamate concentrations throughout the experiments. An antagonist for the NMDA glycine site, SM-31900, attenuated infarction size, suggesting that glycine operated via NMDA receptor. [Conclusions] There is a direct correlation between ischemic injury and extracellular glycine concentration maintained by the GCS.
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