Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration

Abstract

Background and purpose: Deferoxamine (DFX) reduces brain edema, neurological deficits, and brain atrophy after intracerebral hemorrhage (ICH) in aged and young rats. Our previous study found that 50 mg/kg is an effective dose in aged rats. In the present study, we explored potential therapeutic time windows and optimal therapeutic durations.

Methods: Aged male Fischer 344 rats (18 months old) sustained an intracaudate injection of 100 microL autologous whole blood, followed by intramuscular DFX or vehicle beginning at different time points, or continuing for different durations. Subgroups of rats were euthanized at day 3 for brain edema measurement and day 56 for brain atrophy determination. Behavioral tests were performed on days 1, 28, and 56 after ICH.

Results: Systemic administration of DFX, when begun within 12 hours after ICH, reduced brain edema. DFX treatment started 2 hours after ICH and administered for >or=7 days attenuated ICH-induced ventricle enlargement, caudate atrophy, and neurological deficits. DFX attenuated ICH-induced brain atrophy and neurological deficits without detectable side effects when begun within 24 hours and administered for 7 days.

Conclusions: To the extent that these results can be translated to humans, the therapeutic time window and the optimal duration for DFX in this aged rat model of ICH may provide useful information for an ongoing DFX-ICH clinical trial.

Figure 1

Brain water (A), sodium (B) and potassium (C) content at 3 days after ICH. Values are expressed as the means ± SD. Contra=contralateral, Ipsi=ipsilateral. #p<0.01 vs. ICH+Vehicle group.

Figure 2

Forelimb placing (A) and corner turn (B) scores prior to ICH, and 1, 28, 56 days after ICH. Values are expressed as the means ± SD. *p<0.05, #p<0.01 vs. ICH+Vehicle group. For forelimb placing, 100%=no deficit, 0%=maximal deficit. For corner turn, 50%=no deficit, 100%=maximal deficit.

Figure 3

A and B: T₂-weighted magnetic resonance images at eight weeks after ICH treated with vehicle (A) or DFX 50 mg/kg starting 4 hours after ICH for 7 days (B); C: Bar graph showing ventricle volume expressed as a percentage of the contralateral side. Values are expressed as the means±SD. *p<0.05, #p<0.01 vs. ICH+Vehicle group.

Figure 4

A and B: Coronal gross H&E sections eight weeks after ICH treated with vehicle (A) or DFX 50 mg/kg starting 4 hours after ICH for 7 days (B); C: Bar graph showing caudate size expressed as a percentage of the contralateral side. Values are expressed as the means±SD. *p<0.05, #p<0.01 vs. ICH+Vehicle group.

Figure 5

DFX therapeutic time window for brain atrophy and functional outcome. A: Forelimb placing test; B: Corner turn test; C: Ventricle volume expressed as a percentage of the contralateral side at eight weeks after ICH; D: Caudate size expressed as a percentage of the contralateral side at eight weeks after ICH. Values are expressed as the means±SD. *p<0.05, #p<0.01 vs. ICH+Vehicle group.