To investigate the effect of adenosine on anoxic damage of brain tissue, energy metabolism in relation to neural activity was studied using hippocampal slices from the guinea-pig. For the index of energy metabolism, adenosine triphosphate and creatine phosphate in each slice were measured and also postsynaptic potentials (population spike potentials) were recorded in the granule cell layer of the slices. After preparation of the slices, one group of slices was incubated for 120 min in standard medium and another in the medium containing adenosine (5 mM). The adenosine triphosphate content of the former group was 8.8 mmol/kg protein whereas that of the latter was 15.8 mmol/kg protein. During deprivation of oxygen and glucose, adenosine triphosphate and creatine phosphate in the control slices and the slices treated with adenosine decreased rapidly. Adenosine did not alter the rate of consumption of high energy phosphates in both slices. The pretreatment of slices with adenosine (5 mM), however, considerably enhanced the recovery of the adenosine triphosphate level during reoxygenation with glucose after deprivation of oxygen and glucose for 15 and 30 min. Postsynaptic potentials in the granule cell layer of the slice were recorded before and after 10, 15, 20 or 25 min deprivation of oxygen and glucose in the control slice and the slices pretreated with adenosine (5 mM) for 60 min. In the control slices, postsynaptic potentials in one of 10 slices could be recorded after 60 min reoxygenation following 15 min anoxia/aglycemia, while postsynaptic potentials in 10 of 15 slices treated with adenosine could be detected even after 15 min of anoxia/aglycemia. Thus the functional recovery of postsynaptic potentials agreed well with the results of the recovery of adenosine triphosphate level in the slices treated with adenosine. These results indicate that adenosine has a protective effect against anoxic/aglycemic damage of brain tissue by facilitating the resynthesis of tissue adenosine triphosphate during the recovery period.