THREE forms of non-injurious ischemic preconditioning were tested for their effects on endogenous antioxidant activity and subsequent ischemic injury. Test ischemia alone, consisting of 1 h occlusion of both carotid arteries (BCAs) and one middle cerebral artery (MCA), elicited an average volume of cerebral infarction of 143.4 +/- 15.0 mm(3) (mean +/- s.e.m.). Twenty minutes occlusion of the MCA only or MCA and BCAs (but not BCAs only) 24h before test ischemia significantly increased the activity of the antioxidant enzyme superoxide dismutase and significantly reduced the cerebral infarction volume. These findings demonstrate that brief focal ischemia can attenuate the injurious impact of subsequent ischemia and that an upregulation of endogenous antioxidant activity may play a key role in this neuroprotective effect.