Iron regulatory Protein (IRP)-1 and IRP2 inhibit ferritin synthesis by binding to an iron responsive element in the 5'-untranslated region of its mRNA. The present study tested the hypothesis that neurons lacking these proteins would be resistant to hydrogen peroxide (H2O2) toxicity. Wild-type cortical cultures treated with 100-300 mu M H2O2 sustained widespread neuronal death, as measured by lactate dehydrogenase assay, and a significant increase in malondialdehyde. Both endpoints were reduced by over 85% in IRP2 knockout Cultures. IRP1 gene deletion had a weaker and variable effect, with approximately 20% reduction in cell death at 300 mu M H2O2. Ferritin expression after H2O2 treatment was increased 1.9- and 6.7-fold in IRP1 and IRP2 knockout Cultures, respectively, compared with wild-type. These results suggest that iron regulatory proteins, particularly IRP2, increase neuronal Vulnerability to oxidative injury. Therapies targeting IRP2 binding to ferritin mRNA may attenuate neuronal loss due to oxidative stress. (C) 2008 Elsevier Inc. All rights reserved.