Hanson L, Roeytenberg A, Martinez PM, Coppes VG, Sweet DC, Rao RJ, Marti DL, Hoekman JD, Matthews RB, Frey WH, Panter SS
Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Jun 9.
Deferoxamine (DFO) is a high-affinity iron chelator FDA approved for treating iron overload. Pre-clinical research suggests systemically administered DFO prevents and treats ischemic stroke damage, as well as intracerebral hemorrhage. However, translation into human trials has been limited, likely due to difficulties with DFO administration. A non-invasive method of intranasal (IN) administration has recently emerged as a rapid way to bypass the blood-brain barrier and target therapeutic agents to the central nervous system. We report here that IN administration targets DFO to the brain, reduces systemic exposure, and that IN DFO prevents and treats stroke damage after middle cerebral artery occlusion (MCAO) in rats. A 6 mg dose of DFO resulted in significantly higher brain concentrations (0.9 to 18.5 microM) at 30 min after IN administration than with intravenous (IV) administration (0.1 to 0.5 microM, p < 0.05). Relative to blood concentration, IN delivery increased targeting of DFO to the cortex approximately 200-fold when compared to IV delivery. Intranasal administration of three 6 mg IN doses of DFO did not result in clinically significant changes blood pressure or heart rate. Pre-treatment with IN DFO (three 6 mg doses) 48 hr prior to MCAO significantly decreased infarct volume by 55% versus control (p < 0.05). Additionally, post-treatment with IN administration of DFO (five 6 mg doses) immediately after reperfusion significantly decreased infarct volume by 55% (p < 0.05). These experiments suggest intranasally administered DFO may be a useful treatment for stroke, and a prophylactic for patients at high risk for stroke.
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