Transcriptional mechanisms of neuroprotection by iron chelators

Abstract

Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown to enhance metabolic recovery in cerebral ischemia models. The precise mechanisms by which these agents exert their effects remains unclear. Recent studies have demonstrated that iron chelators activate a hypoxia signal transduction pathway that culminates in the stabilization of the transcriptional activator hypoxia‐inducible factor‐1 (HIF‐1) and increased expression of genes that mediate hypoxic adaptation. Previous studies from our lab have shown that structurally distinct iron chelators deferoxamine mesylate and mimosine prevent apoptosis induced by glutathione depletion and oxidative stress in embryonic neuronal cultures. The protective effects are correlated with their ability to enhance DNA binding of HIF‐1 and activating transcription factor (ATF‐1)/cAMP response element‐binding protein (CREB) to the hypoxia response element in cortical cultures and the H19‐7 hippocampal neuronal cell line. mRNA, protein and/or activity levels for genes known to be regulated by HIF‐1, including glycolytic enzymes, p21 waf1/cip1, and erythropoetin, are increased in neuronal cultures in response to iron chelator treatment. Cobalt chloride, which also activates HIF‐1 and ATF1/CREB in cortical cultures, also prevents oxidative stress‐induced death in these cells. Together, these results suggest that iron chelators exert their neuroprotective effects, in part, by activating a signal transduction pathway leading to increased expression of genes known to compensate for hypoxic or oxidative stress. Molecular manipulations are underway to determine whether HIF‐1 is necessary and/or sufficient for cell survival in response to stress in neurons.