Proteomic approach to the study of neuroprotection following intranasal deferoxamine Conference Paper uri icon

abstract

  • Deferoxamine (DFO), an efficient iron (III) and aluminum (III) chelator has shown promise as a protective agent for neurological conditions. DFO is FDA approved for the treatment of iron-overload anemias and has been used to extend and improve the quality of life for these patients for over 40 years. Recent animal studies have demonstrated that acute intranasal administration of DFO induces neuroprotection in rat models of ischemic stroke and chronic administration leads to an improvement in the spatial memory of APP/PS1 (amyloid), P301L tau model of AD and in C57 mice. However, it is not yet clear how intranasally delivered DFO specifically induces neuroprotection in the CNS. To investigate potential mechanisms, we followed changes in the concentration and phosphorylation status of target proteins after a single dose of intranasal DFO. We administered 10% DFO to C57 mice and collected the brain cortex at multiple time points between 30 minutes and 24 hours following administration. Changes in the proteomic signature were analyzed with Fullmoon Biosystem's Explorer S1 antibody arrays (562 targets). We found acute DFO triggered the phosphorylation of a significant number of proteins within 30 minutes with additional changes appearing at the longer time points. Many of these proteins are associated with the regulation of the cell cycle and apoptosis, including AKT, Cdk2, Rb, p53, PTEN, GSK3-beta and NF-kappaB. Shifts in other proteins/signaling pathways support additional mechanisms for the induction of neuroprotection. These results help focus efforts to dissect the mechanisms of neuroprotection through intranasal DFO.

publication date

  • 2011