Excitotoxicity is a major contributor to cell death during the acute phase of
ischemic stroke but aggressive pharmacological targeting of excitotoxicity has failed clinically. Here we investigated whether pretreatment with low doses of
memantine, within the range currently used and well tolerated for the treatment of
Alzheimer's disease, produce a protective effect in
stroke. A coculture preparation exposed to modeled
ischemia showed cell death associated with rapid
glutamate rises and cytotoxic Ca(2+) influx. Cell death was significantly enhanced in the presence of high
memantine concentrations. However, low
memantine concentrations significantly protected neurons and glia via excitotoxic cascade interruption. Mice were systemically administered a range of
memantine doses (0.02, 0.2, 2, 10, and 20 mg/kg/day) starting 24 hours before 60 minutes reversible focal
cerebral ischemia and continuing for a 48-hour recovery period. Low dose (0.2 mg/kg/day)
memantine treatment significantly reduced lesion volume (by 30% to 50%) and improved behavioral outcomes in
stroke lesions that had been separated into either small/striatal or large/striatocortical
infarcts. However, higher doses of
memantine (20 mg/kg/day) significantly increased injury. These results show that clinically established low doses of
memantine should be considered for patients 'at risk' of
stroke, while higher doses are contraindicated.