Effect of glycine and glycine receptor antagonists on NMDA-induced brain injury.
In postnatal day 7 rats, a unilateral intrastriatal injection of 12.5 nmol of N-methyl-D-aspartate (NMDA) reproducibly injures the ipsilateral striatum, adjacent hippocampus and overlying cortex. The severity of injury can be quantified by comparing cerebral hemisphere weights in animals sacrificed 5 days after the injection. Co-injection of NMDA and the glycine receptor antagonists kynurenic acid (KYN) or 7-chlorokynurenic acid (7-CKA) reduced the severity of NMDA-induced damage in a dose-dependent fashion. One hundred nmol of KYN with 12.5 nmol of NMDA reduced average % damage from 19.3 +/- 0.9% (n = 9) to 2.3 +/- 0.5% (n = 6), P less than 0.001, ANOVA. Co-injection of 40 nmol of 7-CKA with 12.5 nmol of NMDA (n = 6) reduced average % damage from 17.1 +/- 1.6% (n = 15) to 3.0 +/- 0.6%, P less than 0.001, ANOVA. Concurrent injection of 1000 nmol glycine with 5 nmol NMDA did not increase the extent of NMDA-induced damage. Our results demonstrate that glycine receptor antagonists attenuate NMDA-induced brain injury in vivo.
Uckele
J E
JE
Department of Pediatrics, University of Michigan, Ann Arbor.
McDonald
J W
JW
Johnston
M V
MV
Silverstein
F S
FS
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000008:administration & dosage*; D007736:Kynurenic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D016202:N-Methylaspartate; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D001224:Aspartic Acid; D016202:N-Methylaspartate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D005998:Glycine