title: Increased concentrations of both NMDA receptor co-agonists D-serine and glycine in global ischemia: a potential novel treatment target for perinatal asphyxia.
abstract: Worldwide, perinatal asphyxia is an important cause of morbidity and mortality among term-born children. Overactivation of the N-methyl-D-aspartate receptor (NMDAr) plays a central role in the pathogenesis of cerebral hypoxia-ischemia, but the role of both endogenous NMDAr co-agonists D-serine and glycine remains largely elusive. We investigated D-serine and glycine concentration changes in rat glioma cells, subjected to oxygen and glucose deprivation (OGD) and CSF from piglets exposed to hypoxia-ischemia by occlusion of both carotid arteries and hypoxia. We illustrated these findings with analyses of cerebrospinal fluid (CSF) from human newborns affected by perinatal asphyxia. Extracellular concentrations of glycine and D-serine were markedly increased in rat glioma cells exposed to OGD, presumably through increased synthesis from L-serine. Upon reperfusion glycine concentrations normalized and D-serine concentrations were significantly lowered. The in vivo studies corroborated the finding of initially elevated and then normalizing concentrations of glycine and decreased D-serine concentrations upon reperfusion These significant increases of both endogenous NMDAr co-agonists in combination with elevated glutamate concentrations, as induced by global cerebral ischemia, are bound to lead to massive NMDAr activation, excitotoxicity and neuronal damage. Influencing these NMDAr co-agonist concentrations provides an interesting treatment target for this common, devastating and currently poorly treatable condition.
authors.affiliation: Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Postbox 85090, 3508 AB, Utrecht, The Netherlands. S.Fuchs@umcutrecht.nl
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Fuchs
authors.forename: Cacha M P C D
authors.initials: CM
authors.lastname: Peeters-Scholte
authors.forename: Martina M J
authors.initials: MM
authors.lastname: de Barse
authors.forename: Martin W
authors.initials: MW
authors.lastname: Roeleveld
authors.forename: Leo W J
authors.initials: LW
authors.lastname: Klomp
authors.forename: Ruud
authors.initials: R
authors.lastname: Berger
authors.forename: Tom J
authors.initials: TJ
authors.lastname: de Koning
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000134:cerebrospinal fluid* / Q000378:metabolism; D045744:Cell Line, Tumor; D005998:Glycine / Q000032:analysis*; D006801:Humans; D000860:Hypoxia; D020925:Hypoxia-Ischemia, Brain / Q000134:cerebrospinal fluid / Q000378:metabolism*; D007231:Infant, Newborn; D009474:Neurons / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015424:Reperfusion; D012127:Respiratory Distress Syndrome, Newborn / Q000134:cerebrospinal fluid / Q000378:metabolism; D012694:Serine / Q000032:analysis*; D013552:Swine
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D005998:Glycine