Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke

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 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.

Fig. 1.

Pretreatment with three 6-mg intranasal doses of 10% DFO under anesthesia 48 h before middle cerebral artery occlusion significantly reduces infarct volume at 5 days after reperfusion. Tissue slices were stained with TTC and areas of infarction appear white. A, pretreatment with intranasally administered water control (n = 9). B, pretreated with intranasally administered DFO (n = 9).

Fig. 2.

Intranasal DFO treatment reduces total, cortical, and striatal infarct volume at 5 days or 48 h after middle cerebral artery occlusion (mean ± S.E.). Intranasal doses were administered under anesthesia. A, pretreatment with three 6-mg intranasal doses of 10% DFO (n = 9) compared with intranasally administered water control (n = 9). B, pretreatment with one 6-mg intranasal dose of 10% DFO (n = 14) compared with intranasally administered water control (n = 12). C, pretreatment with three 1.8-mg intranasal doses of 3% DFO (n = 14) compared with intranasally administered water control (n = 14). D, post-treatment with six 6-mg intranasal doses of 10% DFO (n = 9) compared with intranasally administered water control (n = 6). p values from Student's unpaired t test with #, p < 0.10, *, p < 0.05, and **, p < 0.01.

Fig. 3.

Intranasal DFO treatment reduces neurologic deficit score at 5 days or 48 h after middle cerebral artery occlusion (mean ± S.E.). Intranasal doses were administered under anesthesia. A, pretreatment with three 6-mg intranasal doses of 10% DFO (n = 9) compared with intranasally administered water control (n = 9). B, pretreatment with one 6-mg intranasal dose of 10% DFO (n = 14) compared with intranasally administered water control (n = 12). C, pretreatment with three 1.8-mg intranasal doses of 3% DFO (n = 14) compared with intranasally administered water control (n = 14). D, post-treatment with six 6-mg intranasal doses of 10% DFO (n = 9) compared with intranasally administered water control (n = 6). p values from Student's unpaired t test with #, p < 0.10 and *, p < 0.05.

Fig. 4.

Intranasal DFO treatment reduces postischemic weight loss at 5 days or 48 h after middle cerebral artery occlusion (mean ± S.E.). Intranasal doses were administered under anesthesia. A, pretreatment with three 6-mg intranasal doses of 10% DFO (n = 9) compared with intranasally administered water control (n = 9). B, pretreatment with one 6-mg intranasal dose of 10% DFO (n = 14) compared with intranasally administered water control (n = 12). C, pretreatment with three 1.8-mg intranasal doses of 3% DFO (n = 14) compared with intranasally administered water control (n = 14). D, post-treatment with six 6-mg intranasal doses of 10% DFO (n = 9) compared with intranasally administered water control (n = 6). p values from Student's unpaired t test with #, p < 0.10 and *, p < 0.05.