Evidence has accumulated suggesting that an altered iron metabolism may play an important role in neuronal injury under pathological conditions. The present study was undertaken to evaluate the possibility that iron mediates oxidative stress and delayed neuronal death in the hippocampal CA1 layer following transient forebrain ischemia for 10 minutes. Mitochondrial free radicals were generated in a biphasic pattern in the CA1 pyramidal neurons at 0.5 - 8 hours and 48 - 60 hours after reperfusion. The late free radical production was accompanied by iron accumulation and blocked by administration of deferoxamine, an iron chelator, or Neu2000, a potent antioxidant derived from aspirin and sulfasalazine. The neuroprotective effect of Neu2000 occurred even when it was delivered 24 hours after reperfusion. The iron accumulation was attributable to upregulation of transferrin receptors in the CA1 neurons and increased iron uptake from the blood. The iron accumulation was not observed in rats with leukopenia following peripheral body x-irradiation excluding the brain. Transient forebrain ischemia also induced an increase in permeability of the blood-brain-barrier and the infiltration of blood inflammatory cells. These present findings suggest that iron transport and deposit mediate the delayed free radical production and neuronal death following transient forebrain ischemia.
