Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration
Masanobu Okauchi, Ya Hua, Richard F Keep, Lewis B Morgenstern, Timothy Schallert, Guohua Xi, Masanobu Okauchi, Ya Hua, Richard F Keep, Lewis B Morgenstern, Timothy Schallert, Guohua Xi
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.
Figures
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 Figure 2
Figure 2
Forelimb placing (A) and corner…
Figure 2
Forelimb placing (A) and corner turn (B) scores prior to ICH, and 1,…
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 Figure 3 Figure 4
Figure 3
A and B: T 2…
Figure 3
A and B: T 2 -weighted magnetic resonance images at eight weeks after…
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…
Figure 4
A and B: Coronal gross H&E sections eight weeks after ICH treated with…
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 Figure 5
Figure 5
DFX therapeutic time window for…
Figure 5
DFX therapeutic time window for brain atrophy and functional outcome. A: Forelimb placing…
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
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Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Aging / physiology*
- Animals
- Atrophy / drug therapy
- Atrophy / etiology
- Atrophy / physiopathology
- Brain Edema / drug therapy
- Brain Edema / etiology
- Brain Edema / physiopathology
- Caudate Nucleus / blood supply
- Caudate Nucleus / drug effects
- Caudate Nucleus / pathology
- Cerebral Hemorrhage / complications
- Cerebral Hemorrhage / drug therapy*
- Cerebral Hemorrhage / physiopathology
- Deferoxamine / pharmacology*
- Deferoxamine / therapeutic use
- Disease Models, Animal
- Drug Administration Schedule
- Lateral Ventricles / drug effects
- Lateral Ventricles / pathology
- Male
- Mental Disorders / drug therapy
- Mental Disorders / etiology
- Mental Disorders / physiopathology
- Movement Disorders / drug therapy
- Movement Disorders / etiology
- Movement Disorders / physiopathology
- Rats
- Rats, Inbred F344
- Siderophores / pharmacology
- Siderophores / therapeutic use
- Time Factors
- Treatment Outcome
Substances
- Siderophores
- Deferoxamine
Related information
Grant support
- R01 NS057539-01A2/NS/NINDS NIH HHS/United States
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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 Figure 3 Figure 4
Figure 3
A and B: T 2…
Figure 3
A and B: T 2 -weighted magnetic resonance images at eight weeks after…
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…
Figure 4
A and B: Coronal gross H&E sections eight weeks after ICH treated with…
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 Figure 5
Figure 5
DFX therapeutic time window for…
Figure 5
DFX therapeutic time window for brain atrophy and functional outcome. A: Forelimb placing…
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
Similar articles
- Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats.Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Okauchi M, et al. Stroke. 2009 May;40(5):1858-63. doi: 10.1161/STROKEAHA.108.535765. Epub 2009 Mar 12. Stroke. 2009. PMID: 19286595 Free PMC article.
- Deferoxamine reduces neuronal death and hematoma lysis after intracerebral hemorrhage in aged rats.Hatakeyama T, Okauchi M, Hua Y, Keep RF, Xi G. Hatakeyama T, et al. Transl Stroke Res. 2013 Oct;4(5):546-53. doi: 10.1007/s12975-013-0270-5. Transl Stroke Res. 2013. PMID: 24187595 Free PMC article.
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- Therapeutic strategies for intracerebral hemorrhage.Li Z, Khan S, Liu Y, Wei R, Yong VW, Xue M. Li Z, et al. Front Neurol. 2022 Nov 4;13:1032343. doi: 10.3389/fneur.2022.1032343. eCollection 2022. Front Neurol. 2022. PMID: 36408517 Free PMC article. Review.
- Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models.Carota G, Distefano A, Spampinato M, Giallongo C, Broggi G, Longhitano L, Palumbo GA, Parenti R, Caltabiano R, Giallongo S, Di Rosa M, Polosa R, Bramanti V, Vicario N, Li Volti G, Tibullo D. Carota G, et al. Antioxidants (Basel). 2022 Aug 18;11(8):1596. doi: 10.3390/antiox11081596. Antioxidants (Basel). 2022. PMID: 36009316 Free PMC article.
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Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Aging / physiology*
- Animals
- Atrophy / drug therapy
- Atrophy / etiology
- Atrophy / physiopathology
- Brain Edema / drug therapy
- Brain Edema / etiology
- Brain Edema / physiopathology
- Caudate Nucleus / blood supply
- Caudate Nucleus / drug effects
- Caudate Nucleus / pathology
- Cerebral Hemorrhage / complications
- Cerebral Hemorrhage / drug therapy*
- Cerebral Hemorrhage / physiopathology
- Deferoxamine / pharmacology*
- Deferoxamine / therapeutic use
- Disease Models, Animal
- Drug Administration Schedule
- Lateral Ventricles / drug effects
- Lateral Ventricles / pathology
- Male
- Mental Disorders / drug therapy
- Mental Disorders / etiology
- Mental Disorders / physiopathology
- Movement Disorders / drug therapy
- Movement Disorders / etiology
- Movement Disorders / physiopathology
- Rats
- Rats, Inbred F344
- Siderophores / pharmacology
- Siderophores / therapeutic use
- Time Factors
- Treatment Outcome
Substances
- Siderophores
- Deferoxamine
Related information
Grant support
- R01 NS057539-01A2/NS/NINDS NIH HHS/United States
- NS-047245/NS/NINDS NIH HHS/United States
- NS-039866/NS/NINDS NIH HHS/United States
- R01 NS039866/NS/NINDS NIH HHS/United States
- R01 NS017760/NS/NINDS NIH HHS/United States
- U01 NS052510/NS/NINDS NIH HHS/United States
- NS-052510/NS/NINDS NIH HHS/United States
- R01 NS047245/NS/NINDS NIH HHS/United States
- R01 NS057539/NS/NINDS NIH HHS/United States
- R01 NS047245-04/NS/NINDS NIH HHS/United States
- NS-057539/NS/NINDS NIH HHS/United States
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Show all 15 grants
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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.
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 Figure 5
Figure 5
DFX therapeutic time window for…
Figure 5
DFX therapeutic time window for brain atrophy and functional outcome. A: Forelimb placing…
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
Similar articles
- Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats.Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Okauchi M, et al. Stroke. 2009 May;40(5):1858-63. doi: 10.1161/STROKEAHA.108.535765. Epub 2009 Mar 12. Stroke. 2009. PMID: 19286595 Free PMC article.
- Deferoxamine reduces neuronal death and hematoma lysis after intracerebral hemorrhage in aged rats.Hatakeyama T, Okauchi M, Hua Y, Keep RF, Xi G. Hatakeyama T, et al. Transl Stroke Res. 2013 Oct;4(5):546-53. doi: 10.1007/s12975-013-0270-5. Transl Stroke Res. 2013. PMID: 24187595 Free PMC article.
- Deferoxamine reduces cavity size in the brain after intracerebral hemorrhage in aged rats.Hatakeyama T, Okauchi M, Hua Y, Keep RF, Xi G. Hatakeyama T, et al. Acta Neurochir Suppl. 2011;111:185-90. doi: 10.1007/978-3-7091-0693-8_31. Acta Neurochir Suppl. 2011. PMID: 21725753
- Efficacy of deferoxamine in animal models of intracerebral hemorrhage: a systematic review and stratified meta-analysis.Cui HJ, He HY, Yang AL, Zhou HJ, Wang C, Luo JK, Lin Y, Tang T. Cui HJ, et al. PLoS One. 2015 May 22;10(5):e0127256. doi: 10.1371/journal.pone.0127256. eCollection 2015. PLoS One. 2015. PMID: 26000830 Free PMC article. Review.
- Deferoxamine therapy for intracerebral hemorrhage.Hua Y, Keep RF, Hoff JT, Xi G. Hua Y, et al. Acta Neurochir Suppl. 2008;105:3-6. doi: 10.1007/978-3-211-09469-3_1. Acta Neurochir Suppl. 2008. PMID: 19066072 Review.
Cited by
- Potential role of IGF-1/GLP-1 signaling activation in intracerebral hemorrhage.Siddiqui EM, Mehan S, Bhalla S, Shandilya A. Siddiqui EM, et al. Curr Res Neurobiol. 2022 Sep 10;3:100055. doi: 10.1016/j.crneur.2022.100055. eCollection 2022. Curr Res Neurobiol. 2022. PMID: 36685765 Free PMC article. Review.
- Brain edema formation and therapy after intracerebral hemorrhage.Wan Y, Holste KG, Hua Y, Keep RF, Xi G. Wan Y, et al. Neurobiol Dis. 2023 Jan;176:105948. doi: 10.1016/j.nbd.2022.105948. Epub 2022 Dec 5. Neurobiol Dis. 2023. PMID: 36481437 Review.
- Therapeutic strategies for intracerebral hemorrhage.Li Z, Khan S, Liu Y, Wei R, Yong VW, Xue M. Li Z, et al. Front Neurol. 2022 Nov 4;13:1032343. doi: 10.3389/fneur.2022.1032343. eCollection 2022. Front Neurol. 2022. PMID: 36408517 Free PMC article. Review.
- Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models.Carota G, Distefano A, Spampinato M, Giallongo C, Broggi G, Longhitano L, Palumbo GA, Parenti R, Caltabiano R, Giallongo S, Di Rosa M, Polosa R, Bramanti V, Vicario N, Li Volti G, Tibullo D. Carota G, et al. Antioxidants (Basel). 2022 Aug 18;11(8):1596. doi: 10.3390/antiox11081596. Antioxidants (Basel). 2022. PMID: 36009316 Free PMC article.
- Neuronal ferroptosis after intracerebral hemorrhage.Ren S, Chen Y, Wang L, Wu G. Ren S, et al. Front Mol Biosci. 2022 Aug 5;9:966478. doi: 10.3389/fmolb.2022.966478. eCollection 2022. Front Mol Biosci. 2022. PMID: 35992267 Free PMC article. Review.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Aging / physiology*
- Animals
- Atrophy / drug therapy
- Atrophy / etiology
- Atrophy / physiopathology
- Brain Edema / drug therapy
- Brain Edema / etiology
- Brain Edema / physiopathology
- Caudate Nucleus / blood supply
- Caudate Nucleus / drug effects
- Caudate Nucleus / pathology
- Cerebral Hemorrhage / complications
- Cerebral Hemorrhage / drug therapy*
- Cerebral Hemorrhage / physiopathology
- Deferoxamine / pharmacology*
- Deferoxamine / therapeutic use
- Disease Models, Animal
- Drug Administration Schedule
- Lateral Ventricles / drug effects
- Lateral Ventricles / pathology
- Male
- Mental Disorders / drug therapy
- Mental Disorders / etiology
- Mental Disorders / physiopathology
- Movement Disorders / drug therapy
- Movement Disorders / etiology
- Movement Disorders / physiopathology
- Rats
- Rats, Inbred F344
- Siderophores / pharmacology
- Siderophores / therapeutic use
- Time Factors
- Treatment Outcome
Substances
- Siderophores
- Deferoxamine
Related information
Grant support
- R01 NS057539-01A2/NS/NINDS NIH HHS/United States
- NS-047245/NS/NINDS NIH HHS/United States
- NS-039866/NS/NINDS NIH HHS/United States
- R01 NS039866/NS/NINDS NIH HHS/United States
- R01 NS017760/NS/NINDS NIH HHS/United States
- U01 NS052510/NS/NINDS NIH HHS/United States
- NS-052510/NS/NINDS NIH HHS/United States
- R01 NS047245/NS/NINDS NIH HHS/United States
- R01 NS057539/NS/NINDS NIH HHS/United States
- R01 NS047245-04/NS/NINDS NIH HHS/United States
- NS-057539/NS/NINDS NIH HHS/United States
- U01 NS052510-03/NS/NINDS NIH HHS/United States
- NS-017760/NS/NINDS NIH HHS/United States
- R01 NS017760-29/NS/NINDS NIH HHS/United States
- R01 NS039866-09/NS/NINDS NIH HHS/United States
Show all 15 grants
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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
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