Attenuation of focal ischemic brain injury in mice deficient in the epsilon1 (NR2A) subunit of NMDA receptor.
The role of glutamate neurotoxicity in cerebral ischemia has long been advocated but still remains controversial, because various glutamate receptor (GluR) antagonists showed inconsistent protective efficacy in brain ischemia models. To address this central issue of ischemic brain damage more directly, we used mutant mice deficient in the GluRepsilon1 (NR2A) subunit of NMDA receptor with or without additional heterozygous mutation in the GluRepsilon2 (NR2B) subunit. Those mutant mice, as well as their littermates, were subjected to focal cerebral ischemia by introducing a 6-0 nylon suture from left common carotid artery. Brain injury volumes after 2 hr of suture insertion, as evaluated by 2,3,5-triphenyltetrazolium chloride staining at 24 hr after ischemia, revealed significantly smaller injury size in GluRepsilon1 subunit knock-out mice compared with their wild-type littermates. The reduction in injury volume was not attributable to differences in body temperature or in blood flow during ischemia. Additional heterozygous GluRepsilon2 subunit disruption did not result in further reduction in injury volume. These data directly demonstrate relevance of NMDA receptor-mediated tissue injury after brain ischemia and provide evidence that GluRepsilon1 subunit is involved in these injurious mechanisms.
Morikawa
E
E
Department of Neurosurgery, University of Tokyo Faculty of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan.
Mori
H
H
Kiyama
Y
Y
Mishina
M
M
Asano
T
T
Kirino
T
T
D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D002545:Brain Ischemia / Q000235:genetics* / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000737:chemistry; D002544:Cerebral Infarction / Q000235:genetics / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009498:Neurotoxins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*
D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid