Stroke trials are initiated after demonstrated pharmacological protection in animal models. NBQX protects CA1 neurons against global ischemia; however, this glutamate antagonist induces a period of subnormal temperature (e.g., a decrease of only 1.0-1.5 degrees C) lasting several days. In this study, NBQX (3 x 30 mg/kg, i.p.) was administered starting 60 min after reperfusion, and brain temperature had declined significantly below vehicle-treated animals by 2 h after reperfusion. When the postischemic brain temperature of NBQX-treated gerbils was regulated, no neuronal protection was found. Mimicking an NBQX-induced temperature profile for 28 h postischemia yielded histological protection 4 days later comparable to that of NBQX. However, both the NBQX and temperature simulation groups showed decreased protection after 10-day survival. Our data suggest that a protracted period of subnormal temperature during postischemic period can obscure the interpretation of preclinical drug studies.