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The Journal of Neuroscience, December 1, 1998, 18(23):9727-9732

Attenuation of Focal Ischemic Brain Injury in Mice Deficient in the 1 (NR2A) Subunit of NMDA Receptor

Eiharu Morikawa^{1, 3, 4}, Hisashi Mori², Yuji Kiyama², Masayoshi Mishina^{2, 4}, Takao Asano³, and Takaaki Kirino^{1, 4}

Departments of ¹ Neurosurgery and ² Molecular Neurobiology and Pharmacology, University of Tokyo Faculty of Medicine, Bunkyo-ku, Tokyo 113-8655, Japan, ³ Department of Neurosurgery, Saitama Medical School/Center, Kawagoe, Saitama 350-8550, Japan, and ⁴ Core Research for Evolution and Technology, Japan Science and Technology Corporation, Kawaguchi, 332-0012, Japan

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 GluR1 (NR2A) subunit of NMDA receptor with or without additional heterozygous mutation in the GluR2 (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 GluR1 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 GluR2 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 GluR1 subunit is involved in these injurious mechanisms.

Key words: NMDA receptor; GluR1 subunit; neurotoxicity; glutamate; brain ischemia; cerebral infarction

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18239727-06$05.00/0

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