N-Tert-butyl-alpha-phenylnitrone (PBN), a spin trap agent, reduced ischemic hippocampal damage and the associated locomotor hyperactivity in Mongolian gerbils. Cerebral ischemia was induced in unanesthetized gerbils by a bilateral 5 min occlusion of the carotid arteries. PBN (100 mg/kg, i.p.) administered 30 min prior to carotid occlusion, prevented the increase in locomotor activity observed in saline-injected ischemic animals and significantly reduced damage to the hippocampal CAI pyramidal cell layer observed 5 days post-ischemia. These findings support the hypothesis of an involvement of reactive free radicals as a significant cause of ischemia-reperfusion-induced cerebral injury and suggest that PBN may be a useful agent for the prevention of cerebral ischemic damage.