The blockade of NMDA receptors has been pursued as a strategy to reduce the consequences of acute ischemic stroke (AIS) and NMDA receptors remain a valid therapeutic target to treat AIS. Because the pharmacological and toxicity profile of memantine in Alzheimer's disease patients appears to be good, we determined whether memantine would be effective at improving behavioral performance following embolic strokes in rabbits. For these studies, we used a rabbit multiple infarct ischemia model with a well-defined behavioral endpoint. In this study, memantine dissolved in PBS was given intravenously either as a bolus injection (over 1 min) or infused over 60 min. The P(50) of the control groups measured 24 h after embolization were 1.12 +/- 0.18 mg and 1.08 +/- 0.23 mg for the bolus injected and infused groups, respectively. Bolus injections of memantine at 1 mg/kg and 10 mg/kg were not effective at altering the P(50) value and memantine at a dose of 25 mg/kg was lethal. However, slowly infused memantine (25 mg/kg) significantly increased the P(50) value to 2.31 +/- 0.48 mg and 3.13 +/- 1.13 mg when given 5 and 60 min following embolization, respectively. Memantine administered 180 min following embolization also increased the P(50) value to 2.69 +/- 2.21 mg, but the response was variable. These results suggest that uncompetitive NMDA antagonists, more specifically open channel blockers, which may be alternatives to high affinity NMDA antagonists, may have substantial therapeutic benefit for the treatment of AIS and memantine or new dual activity analogs of memantine should be further pursued as a useful therapy to treat the behavioral deficits associated with multiple-infarct ischemia.