Direct correlation between ischemic injury and extracellular glycine concentration in mice with genetically altered activities of the glycine cleavage multienzyme system

Masaya Oda, Shigeo Kure, Taku Sugawara, Suguru Yamaguchi, Kanako Kojima, Toshikatsu Shinka, Kenichi Sato, Ayumi Narisawa, Yoko Aoki, Yoichi Matsubara, Tomoya Omae, Kazuo Mizoi, Hiroyuki Kinouchi

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE - Ischemia elicits the rapid release of various amino acid neurotransmitters. A glutamate surge activates N-methyl-d-aspartate (NMDA) glutamate receptors, triggering deleterious processes in 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 multienzyme system (GCS), which plays a fundamental role in maintaining extracellular glycine concentration. 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 neuronal injury after transient occlusion of the middle cerebral artery in these mice by measuring extracellular amino acid concentrations in microdialysates. RESULTS - High-GCS and low-GCS mice had significantly lower and higher basal concentrations of extracellular glycine than did controls, respectively. In low-GCS mice, the extracellular glycine concentration reached 2-fold of control levels during ischemia, and infarct volume was significantly increased by 69% with respect to controls. In contrast, high-GCS mice had a significantly smaller infarct 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 infarct size, suggesting that glycine operated via the NMDA receptor. CONCLUSIONS - There is a direct correlation between ischemic injury and extracellular glycine concentration maintained by the GCS.

Original languageEnglish
Pages (from-to)2157-2164
Number of pages8
JournalStroke
Volume38
Issue number7
DOIs
Publication statusPublished - 2007 Jul

Keywords

  • Animal models
  • Glutamate
  • Glycine
  • NMDA glutamate receptor
  • Neuroprotection
  • Reperfusion
  • Transgenic mice

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialised Nursing

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