Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model.
The neuroprotective effects of YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)6-nitro-1,2,3,4-tetrahydro-1-quinoxal inyl]acetic acid monohydrate), a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist with high water solubility, were examined in rats with transient middle cerebral artery (MCA) occlusion. The right MCA of male SD rats was occluded for 3 h using the intraluminal suture occlusion method. YM872 significantly reduced the infarct volume 24 hours after occlusion, at dosages of 20 and 40 mg/kg/h (iv infusion) when given for 4 h immediately after occlusion. Furthermore, delayed administration of YM872 (20 mg/kg/h iv infusion for 4 h, starting 2 or 3 h after the occlusion) also reduced the infarct volume and the neurological deficits measured at 24 h. Additionally, the therapeutic efficacy of YM872 persisted for at least seven days after MCA occlusion in animals treated with YM872 for 4 h starting 2 h after MCA occlusion. These data demonstrate that AMPA receptors contribute to the development of neuronal damage after reperfusion as well as during ischemia in the focal ischemia models and that the acute effect of the blockade of AMPA receptors persists over a long time period. YM872 shows promise as an effective treatment for patients suffering from acute stroke.
Kawasaki-Yatsugi
S
S
Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. yatsugis@yamanouchi.co.jp
Ichiki
C
C
Yatsugi
S
S
Takahashi
M
M
Shimizu-Sasamata
M
M
Yamaguchi
T
T
Minematsu
K
K
D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000517:prevention & control*; D002536:Cerebral Arteries / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000150:complications / Q000517:prevention & control; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control
D007093:Imidazoles; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; C110629:YM 872