ALTHOUGH several studies have shown that L-threo-3,4-dihydroxyphenylserine (DOPS) may provide a neuroprotective effect against ischemic brain damage, its protective mechanism is not fully understood. Glutamate release and hippocampal blood flow in ischemia with administration of DOPS were investigated to elucidate the neuroprotective mechanism of DOPS. Pre- (but not post-) ischemic administration of DOPS rescued 73% of hippocampal CA1 neurons (p< 0.001, compared with ischemia only) 1 week after transient global ischemia in gerbils. While glutamate release induced by ischemia was not affected, the increase of hippocampal blood flow during reperfusion was significantly suppressed by DOPS. These results demonstrate that DOPS may prevent reperfusion injury by suppression of hyperemia after ischemia, resulting in neuroprotection.