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-nitr o-1,2,3,4-tetrahydro-1-quinoxalinyl]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 cer ebral artery (MCA) occlusion. The right MCA of male SD rats was occluded fo r 3 h using the intraluminal suture occlusion method. YM872 significantly r educed 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. Furt hermore, delayed administration of YM872 (20 mg/kg/h iv infusion for 4 h, s tarting 2 or 3 h after the occlusion) also reduced the infarct volume and t he neurological deficits measured at 24 h. Additionally, the therapeutic ef ficacy of YM872 persisted for at least seven days after MCA occlusion in an imals treated with YM872 for 4 h starting 2 h after MCA occlusion. These da ta demonstrate that AMPA receptors contribute to the development of neurona l damage after reperfusion as well as during ischemia in the focal ischemia models and that the acute effect of the blockade of AMPA receptors persist s over a long time period. YM872 shows promise as an effective treatment fo r patients suffering from acute stroke. (C) 2000 Elsevier Science Ltd. All rights reserved.