Systemic administration of propentofylline (PPF), an adenosine uptake inhibitor, has been demonstrated to protect CA1 pyramidal cells from death following transient cerebral ischemia in gerbils. In order to examine the direct effects of this inhibitor, we tested whether or not PPF administered into the hippocampus in situ through a microdialysis probe could attenuate ischemia-induced excitatory amino acid (EAA) release and prevent subsequent death of CA1 pyramidal cells in the gerbil. The EAA release and death of CA1 pyramidal cells observed in the hippocampus were compared with those in the contralateral hippocampus of the same animal into which vehicle alone was administered. The results indicated that pre- as well as post-treatments with PPF inhibited the death of CA1 pyramidal cells after 5-min ischemia in a dose-dependent manner, but did not significantly alter the EAA release during ischemia and reperfusion in the same animals. While the neuroprotective effect of PPF against ischemic damage has commonly been ascribed to attenuation of EAA release during ischemia, other actions of adenosine such as those influencing the synaptic responses, neuronal excitation, and local cerebral circulation, or as yet unidentified actions may be involved in the observed neuroprotective effects of PPF.