Abstract The effects of histamine (HA) receptor antagonists on hypoxia + hypoglycemia (ischemia)-induced impairment of 2-deoxyglucose (2-DG) uptake by rat hippocampal slices was evaluated. Hippocampal slices were exposed to 20-min ischemia and then returned to oxygenated and glucose-containing Krebs-Ringer solution for 6 h. Ischemia reduced 2-DG uptake in the hippocampal slices. The ischemia-induced reduction in 2-DG uptake was attenuated by pretreatment with H 1 receptor antagonist but not with H 2 receptor antagonist. Treatment with HA exacerbated the ischemia-induced decrease. The H 1 receptor antagonist-induced neuroprotective effect was blocked by co-treatment with HA. The present study suggests that the blockade of H 1 receptor-mediated function has a protective role in ischemia-induced decreases in glucose metabolism in hippocampal slices.