The effect of propentofylline, an adenosine uptake inhibitor, on ischemic tolerance was investigated in the gerbil global ischemia model. Propentofylline was administered 24 hours after short preconditioning ischemia, and animals were subjected to 5-minute ischemia 24 hours thereafter. Propentofylline at a dose of 20 mg/kg intraperitoneally, but not at a dose of 10 mg/kg, significantly potentiated the protective effect of preconditioning ischemia in the CA1 hippocampal neurons. This effect was completely abolished by simultaneous administration of theophylline (20 mg/kg), an adenosine receptor blocker. This finding suggests the involvement of adenosine receptor for the development of ischemic tolerance.