title: Direct correlation between ischemic injury and extracellular glycine concentration in mice with genetically altered activities of the glycine cleavage multienzyme system.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Seiryomachi, Aobaku, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Oda
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.forename: Taku
authors.initials: T
authors.lastname: Sugawara
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Kanako
authors.initials: K
authors.lastname: Kojima
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Shinka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sato
authors.forename: Ayumi
authors.initials: A
authors.lastname: Narisawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Tomoya
authors.initials: T
authors.lastname: Omae
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mizoi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kinouchi
mesh_terms: D000409:Alanine / Q000134:cerebrospinal fluid; D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D002522:Chlorocebus aethiops; D018698:Glutamic Acid / Q000134:cerebrospinal fluid; D005998:Glycine / Q000134:cerebrospinal fluid*; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow; D013654:Taurine / Q000134:cerebrospinal fluid; D014166:Transferases / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000134:cerebrospinal fluid
chemical_list: D002352:Carrier Proteins; D007211:Indoles; D009097:Multienzyme Complexes; D016194:Receptors, N-Methyl-D-Aspartate; C466317:SM 31900; C064525:glycine cleavage system; D013654:Taurine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000594:Amino Acid Oxidoreductases; D050841:Glycine Dehydrogenase (Decarboxylating); D014166:Transferases; D000409:Alanine; D005998:Glycine