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Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice

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Abstract

Intranasal administration, which bypasses the blood–brain barrier and minimizes systemic exposure, is a non-invasive alternative for targeted drug delivery to the brain. While identification of metal dysregulation in Alzheimer’s brain has led to the development of therapeutic metal-binding agents, targeting to the brain has remained an issue. The purpose of this study was to both determine concentrations of deferoxamine (DFO), a high-affinity iron chelator, reaching the brains of mice after intranasal administration and to determine its efficacy in a mouse model of spatial memory loss. Intranasal administration of DFO (2.4 mg) labeled with 59Fe (75 μCi) to C57 mice resulted in micromolar concentrations at 30 min within brain parenchyma. After 3 months of intranasal DFO treatment, 2.4 mg three times per week, 48-week-old APP/PS1 mice had significantly reduced escape latencies in Morris water maze compared to vehicle-treated mice. This is the first report that intranasal DFO improves spatial memory in a mouse model of Alzheimer’s disease and demonstrates that intranasal DFO reaches the brain in therapeutic doses.

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Acknowledgments

Thanks to Julian Tokarev and Kate Faltesek for their help with the behavior tests. Thanks to Thomas Flottemesch for assistance with the statistical analyses. Funding for this work was received from the HealthPartners Research Foundation Internal Grant 05-097 and private donations made to the Alzheimer’s Research Center at Regions Hospital.

Ethical standards

All experimental procedures were in compliance with the Guide for the Care and Use of Laboratory Animals and approved by the AAALAC accredited Health Partners Research Foundation’s Animal Care and Use Program.

Declaration of interest

LRH, SSP, and WHF are inventors on patents owned by the HealthPartners Research Foundation related to intranasal deferoxamine. All authors, except SSP, were employed by the HealthPartners Research Foundation during the time this work was conducted.

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Authors and Affiliations

  1. Alzheimer’s Research Center at Regions Hospital, HealthPartners Research Foundation, 640 Jackson Street, St. Paul, MN, 55101, USA

    Leah R. Hanson, Jared M. Fine, Dan B. Renner, Aleta L. Svitak, Rachel B. Burns, Thuhien M. Nguyen, Nathan J. Tuttle, Dianne L. Marti & William H. Frey II

  2. Department of Neurosurgery, San Francisco Veterans Affairs Medical Center and the University of California at San Francisco, 4150 Clement Avenue, San Francisco, CA, 94121, USA

    S. Scott Panter

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  1. Leah R. Hanson
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Correspondence to Leah R. Hanson.

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Hanson, L.R., Fine, J.M., Renner, D.B. et al. Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice. Drug Deliv. and Transl. Res. 2, 160–168 (2012). https://doi.org/10.1007/s13346-011-0050-2

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