Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke.
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 microM) at 30 min after intranasal administration than after intravenous administration (0.1-0.5 microM, 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.
Hanson
Leah R
LR
Alzheimer's Research Center at Regions Hospital, HealthPartners Research Foundation, St. Paul, Minnesota 55101, USA. Leah.R.Hanson@HealthPartners.com
Roeytenberg
Annina
A
Martinez
Paula M
PM
Coppes
Valerie G
VG
Sweet
Donald C
DC
Rao
Reshma J
RJ
Marti
Dianne L
DL
Hoekman
John D
JD
Matthews
Rachel B
RB
Frey
William H
WH
Panter
S Scott
SS
D000281:Administration, Intranasal; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000150:complications*; D003676:Deferoxamine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D007504:Iron Radioisotopes; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D020521:Stroke / Q000209:etiology* / Q000517:prevention & control*; D014018:Tissue Distribution
D007504:Iron Radioisotopes; D018696:Neuroprotective Agents; D003676:Deferoxamine