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Research ArticleNEUROPHARMACOLOGY

Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke

Leah R. Hanson, Annina Roeytenberg, Paula M. Martinez, Valerie G. Coppes, Donald C. Sweet, Reshma J. Rao, Dianne L. Marti, John D. Hoekman, Rachel B. Matthews, William H. Frey II and S. Scott Panter
Journal of Pharmacology and Experimental Therapeutics September 2009, 330 (3) 679-686; DOI: https://doi.org/10.1124/jpet.108.149807
Leah R. Hanson
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Annina Roeytenberg
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Paula M. Martinez
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Valerie G. Coppes
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Donald C. Sweet
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Reshma J. Rao
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Dianne L. Marti
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John D. Hoekman
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Rachel B. Matthews
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William H. Frey II
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S. Scott Panter
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Abstract

Deferoxamine (DFO) is a high-affinity iron chelator approved by the Food and Drug Administration for treating iron overload. Preclinical research suggests that systemically administered DFO prevents and treats ischemic stroke damage and intracerebral hemorrhage. However, translation into human trials has been limited, probably because of difficulties with DFO administration. A noninvasive method of intranasal administration has emerged recently as a rapid way to bypass the blood-brain barrier and target therapeutic agents to the central nervous system. We report here that intranasal administration targets DFO to the brain and reduces systemic exposure, and that intranasal DFO prevents and treats stroke damage after middle cerebral artery occlusion (MCAO) in rats. A 6-mg dose of DFO resulted in significantly higher DFO concentrations in the brain (0.9–18.5 μM) at 30 min after intranasal administration than after intravenous administration (0.1–0.5 μM, p < 0.05). Relative to blood concentration, intranasal delivery increased targeting of DFO to the cortex approximately 200-fold compared with intravenous delivery. Intranasal administration of three 6-mg doses of DFO did not result in clinically significant changes in blood pressure or heart rate. Pretreatment with intranasal DFO (three 6-mg doses) 48 h before MCAO significantly decreased infarct volume by 55% versus control (p < 0.05). In addition, post-treatment with intranasal administration of DFO (six 6-mg doses) immediately after reperfusion significantly decreased infarct volume by 55% (p < 0.05). These experiments suggest that intranasally administered DFO may be a useful treatment for stroke, and a prophylactic for patients at high risk for stroke.

Footnotes

  • This work was supported by the National Institutes of Health [Grant R21-NS04761401A1] and by the Alzheimer's Research Center.

  • L.R.H., A.R., W.H.F., and S.S.P. have filed a patent related to the findings discussed in this article.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.149807.

  • ABBREVIATIONS: DFO, deferoxamine; MCAO, middle cerebral artery occlusion; CNS, central nervous system; BBB, blood-brain barrier; HIF-1α, hypoxia-inducible factor; TTC, 2,3,5-triphenyltetrazolium chloride; ECA, external carotid artery; CABG, coronary artery bypass graft.

    • Received January 7, 2009.
    • Accepted June 4, 2009.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticleNEUROPHARMACOLOGY

Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke

Leah R. Hanson, Annina Roeytenberg, Paula M. Martinez, Valerie G. Coppes, Donald C. Sweet, Reshma J. Rao, Dianne L. Marti, John D. Hoekman, Rachel B. Matthews, William H. Frey and S. Scott Panter
Journal of Pharmacology and Experimental Therapeutics September 1, 2009, 330 (3) 679-686; DOI: https://doi.org/10.1124/jpet.108.149807

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Research ArticleNEUROPHARMACOLOGY

Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke

Leah R. Hanson, Annina Roeytenberg, Paula M. Martinez, Valerie G. Coppes, Donald C. Sweet, Reshma J. Rao, Dianne L. Marti, John D. Hoekman, Rachel B. Matthews, William H. Frey and S. Scott Panter
Journal of Pharmacology and Experimental Therapeutics September 1, 2009, 330 (3) 679-686; DOI: https://doi.org/10.1124/jpet.108.149807
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