Neuroprotective effect of YM90K, an AMPA-receptor antagonist, against delayed neuronal death induced by transient global cerebral ischemia in gerbils and rats.
We investigated the neuroprotective effect of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor antagonist YM90K in transient global ischemia models. In a gerbil model, transient ischemia was induced by bilateral common carotid artery (CCA) occlusion for 5 min. On administration at 1 hr after ischemia, the AMPA antagonists NBQX (30 mg/kg, i.p. x 3) and YM90K (15 mg/kg, i.p. x 3 or 30 mg/kg, i.p. x 3) significantly reduced the delayed neuronal death in the hippocampal CA1 region from 4 days after bilateral CCA occlusion. Furthermore, YM90K (30 mg/kg, i.p. x 3) showed a neuroprotective effect even when given at 6 hr after ischemia. In contrast, the N-methyl-D-aspartate receptor antagonists CGS19755, MNQX (30 mg/kg, i.p. x 3, each) and (+/-)MK-801 (10 mg/kg, i.p.) were not effective on injection at 1 hr after ischemia in this model. In a rat model, ischemia was induced by 4-vessel occlusion (4-VO) for 10 min. YM90K was administered 60 min after reperfusion. Rectal and temporal muscle temperatures were maintained at the same level as in the control group for 6 hr. YM90K markedly prevented the development of delayed neuronal death from 7 days after 4-VO at doses of 15 or 30 mg/kg, i.p. x 3, with neuroprotective efficacy similar to that in the gerbil model. These results suggest that the AMPA receptor plays a critical role in the development of the delayed neuronal death induced by transient global cerebral ischemia. They also suggest that the neuroprotective effect of YM90K is not related to its hypothermic effect.
Kawasaki-Yatsugi
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S
Neuroscience Research, Pharmacological Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Yatsugi
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S
Koshiya
K
K
Shimizu-Sasamata
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M
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione