The aim of the present investigation was to assess neuroprotection exerted by diazepam (0.1-25 microM) in rat cortical brain slices subjected to oxygen-glucose deprivation and reoxygenation. Neuronal injury and neuroprotection were assessed by measuring the release of glutamate and lactate dehydrogenase and tissue water content. Results demonstrate that diazepam exerted neuroprotective effects according to a "U-shaped", hormetic-like, concentration-response curve, with an efficacy window of 0.5-5 microM concentration. Flumazenil (20 microM) fully antagonised neuroprotection afforded by 5 microM diazepam. In conclusion, the hormetic response of diazepam should be taken into consideration when designing experiments aimed at assessing diazepam neuroprotection against ischemia/reoxygenation injury.