NEUROPROTECTIVE EFFICACY OF YM872, AN LPHA-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONIC ACID RECEPTOR ANTAGONIST, AFTER PERMANENT MIDDLE CEREBRAL-ARTERY OCCLUSION IN RATS

The neuroprotective efficacy of YM872, a novel, highly water-soluble l pha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antago nist, was investigated in rats subjected to permanent occlusion of the left middle cerebral artery. The rats were assessed either histologic ally or neurologically 24 hr or 1 wk after ischemia. YM872 was intrave nously infused for either 4 or 24 hr at dose rates of 0 to 20 mg/kg/hr starting 5 min after ischemia to examine the effect of prolonged trea tment. YM872 was then infused at 20 mg/kg/hr beginning 0 to 4 hr after ischemia to determine the efficacy time window. Additionally, a 20 mg /kg/hr dose rate of YM872 was infused for 4 hr in single day- or 5-day repetitive-administrations to evaluate long-term benefits of the drug . YM872 significantly reduced infarct volume in both 4- and 24-hr trea tment groups measured 24 hr after ischemia. No difference was observed in the degree of protection between length of infusion. Significant n europrotection was maintained even when drug administration was delaye d up to 2 hr after ischemia. A single YM872-administration significant ly improved neurological deficit and reduced infarct volume (30%, P <. 01) measured 1 wk after ischemia. YM872 treatment did not induce such adverse effects as physiological changes, serious behavioral abnormali ties or nephrotoxicity. These data suggest that the alpha-amino-3-hydr oxy5-methylisoxazole-4-propionic acid receptor plays a crucial role in the progression of neuronal damage in the early phase of ischemia and that YM872 may be useful in treating acute ischemic stroke.