Skip to main content
Top
Published in: Translational Stroke Research 1/2019

01-02-2019 | Original Article

Brain Ceruloplasmin Expression After Experimental Intracerebral Hemorrhage and Protection Against Iron-Induced Brain Injury

Authors: Hongwei Liu, Ya Hua, Richard F. Keep, Guohua Xi

Published in: Translational Stroke Research | Issue 1/2019

Login to get access

Abstract

Ceruloplasmin (CP) is an essential ferroxidase that is involved in maintaining iron homeostasis by oxidizing toxic ferrous iron (Fe2+) to less-toxic ferric iron (Fe3+). CP has been well studied in many neurodegenerative diseases, but there has not been an in-depth investigation in intracerebral hemorrhage (ICH). This research investigated brain CP expression in rats after ICH and the effect of CP on Fe2+-induced brain injury. This study had two parts: first, rats had injection of autologous blood into the right basal ganglia and the time course of CP expression in the brain examined (protein and mRNA). Second, rats had an injection of either Fe2+ in saline, Fe2+ plus CP in saline, or saline alone into the right basal ganglia. All rats in the second part had T2-weighted magnetic resonance imaging, and behavioral tests before the brains were harvested for immunohistochemistry and Western blotting. We found that CP was expressed on neurons and astrocytes in both cortex and basal ganglia after ICH. The time course showed that ICH induced CP expression increased from 4 h to 7 days, peaking at day 3. Whether the brain itself can produce CP was confirmed by RT-PCR. Exogenous CP reduced Fe2+-induced T2 lesions, blood-brain barrier disruption, brain cell death, and neurological deficits. These results suggest a role of CP in potentially reducing ICH-induced brain injury.
Literature
1.
go back to reference Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurol. 2006;5:53–63.CrossRef Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurol. 2006;5:53–63.CrossRef
2.
go back to reference Wilkinson DA, Pandey AS, Thompson BG, Keep RF, Hua Y, Xi G. Injury mechanisms in acute intracerebral hemorrhage. Neuropharmacology. 2018;134:240–8.CrossRef Wilkinson DA, Pandey AS, Thompson BG, Keep RF, Hua Y, Xi G. Injury mechanisms in acute intracerebral hemorrhage. Neuropharmacology. 2018;134:240–8.CrossRef
3.
go back to reference Garton T, Keep RF, Wilkinson DA, Strahle JM, Hua Y, Garton HJ, et al. Intraventricular hemorrhage: the role of blood components in secondary injury and hydrocephalus. Transl Stroke Res. 2016;7:447–51.CrossRef Garton T, Keep RF, Wilkinson DA, Strahle JM, Hua Y, Garton HJ, et al. Intraventricular hemorrhage: the role of blood components in secondary injury and hydrocephalus. Transl Stroke Res. 2016;7:447–51.CrossRef
4.
go back to reference Xiong XY, Wang J, Qian ZM, Yang QW. Iron and intracerebral hemorrhage: from mechanism to translation. Transl Stroke Res. 2014;5:429–41.CrossRef Xiong XY, Wang J, Qian ZM, Yang QW. Iron and intracerebral hemorrhage: from mechanism to translation. Transl Stroke Res. 2014;5:429–41.CrossRef
5.
go back to reference Bielli P, Calabrese L. Structure to function relationships in ceruloplasmin: a ‘moonlighting’ protein. Cell Mol Life Sci. 2002;59:1413–27.CrossRef Bielli P, Calabrese L. Structure to function relationships in ceruloplasmin: a ‘moonlighting’ protein. Cell Mol Life Sci. 2002;59:1413–27.CrossRef
6.
go back to reference Klomp LW, Farhangrazi ZS, Dugan LL, Gitlin JD. Ceruloplasmin gene expression in the murine central nervous system. J Clin Invest. 1996;98:207–15.CrossRef Klomp LW, Farhangrazi ZS, Dugan LL, Gitlin JD. Ceruloplasmin gene expression in the murine central nervous system. J Clin Invest. 1996;98:207–15.CrossRef
7.
go back to reference Texel SJ, Xu X, Harris ZL. Ceruloplasmin in neurodegenerative diseases. Biochem Soc Trans. 2008;36:1277–81.CrossRef Texel SJ, Xu X, Harris ZL. Ceruloplasmin in neurodegenerative diseases. Biochem Soc Trans. 2008;36:1277–81.CrossRef
8.
go back to reference Zheng M, Du H, Ni W, Koch LG, Britton SL, Keep RF, et al. Iron-induced necrotic brain cell death in rats with different aerobic capacity. Transl Stroke Res. 2015;6:215–23.CrossRef Zheng M, Du H, Ni W, Koch LG, Britton SL, Keep RF, et al. Iron-induced necrotic brain cell death in rats with different aerobic capacity. Transl Stroke Res. 2015;6:215–23.CrossRef
9.
go back to reference Jin H, Xi G, Keep RF, Wu J, Hua Y. Darpp-32 to quantify intracerebral hemorrhage-induced neuronal death in basal ganglia. Transl Stroke Res. 2013;4:130–4.CrossRef Jin H, Xi G, Keep RF, Wu J, Hua Y. Darpp-32 to quantify intracerebral hemorrhage-induced neuronal death in basal ganglia. Transl Stroke Res. 2013;4:130–4.CrossRef
10.
go back to reference Dang G, Yang Y, Wu G, Hua Y, Keep RF, Xi G. Early erythrolysis in the hematoma after experimental intracerebral hemorrhage. Transl Stroke Res. 2017;8:174–82.CrossRef Dang G, Yang Y, Wu G, Hua Y, Keep RF, Xi G. Early erythrolysis in the hematoma after experimental intracerebral hemorrhage. Transl Stroke Res. 2017;8:174–82.CrossRef
11.
go back to reference Hua Y, Xi G, Keep RF, Wu J, Jiang Y, Hoff JT. Plasminogen activator inhibitor-1 induction after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab. 2002;22:55–61.CrossRef Hua Y, Xi G, Keep RF, Wu J, Jiang Y, Hoff JT. Plasminogen activator inhibitor-1 induction after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab. 2002;22:55–61.CrossRef
12.
go back to reference Ni W, Zheng M, Xi G, Keep RF, Hua Y. Role of lipocalin-2 in brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2015;35:1454–61.CrossRef Ni W, Zheng M, Xi G, Keep RF, Hua Y. Role of lipocalin-2 in brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2015;35:1454–61.CrossRef
13.
go back to reference Wan S, Cheng Y, Jin H, Guo D, Hua Y, Keep RF, et al. Microglia activation and polarization after intracerebral hemorrhage in mice: the role of protease-activated receptor-1. Transl Stroke Res. 2016;7:478–87.CrossRef Wan S, Cheng Y, Jin H, Guo D, Hua Y, Keep RF, et al. Microglia activation and polarization after intracerebral hemorrhage in mice: the role of protease-activated receptor-1. Transl Stroke Res. 2016;7:478–87.CrossRef
14.
go back to reference Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G. Behavioral tests after intracerebral hemorrhage in the rat. Stroke. 2002;33:2478–84.CrossRef Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G. Behavioral tests after intracerebral hemorrhage in the rat. Stroke. 2002;33:2478–84.CrossRef
15.
go back to reference Altamura C, Squitti R, Pasqualetti P, Gaudino C, Palazzo P, Tibuzzi F, et al. Ceruloplasmin/transferrin system is related to clinical status in acute stroke. Stroke. 2009;40:1282–8.CrossRef Altamura C, Squitti R, Pasqualetti P, Gaudino C, Palazzo P, Tibuzzi F, et al. Ceruloplasmin/transferrin system is related to clinical status in acute stroke. Stroke. 2009;40:1282–8.CrossRef
16.
go back to reference Kristinsson J, Snaedal J, Torsdottir G, Johannesson T. Ceruloplasmin and iron in Alzheimer’s disease and Parkinson’s disease: a synopsis of recent studies. Neuropsychiatr Dis Treat. 2012;8:515–21.PubMedPubMedCentral Kristinsson J, Snaedal J, Torsdottir G, Johannesson T. Ceruloplasmin and iron in Alzheimer’s disease and Parkinson’s disease: a synopsis of recent studies. Neuropsychiatr Dis Treat. 2012;8:515–21.PubMedPubMedCentral
17.
go back to reference Vassiliev V, Harris ZL, Zatta P. Ceruloplasmin in neurodegenerative diseases. Brain Res Rev. 2005;49:633–40.CrossRef Vassiliev V, Harris ZL, Zatta P. Ceruloplasmin in neurodegenerative diseases. Brain Res Rev. 2005;49:633–40.CrossRef
18.
go back to reference Kaneko K, Hineno A, Yoshida K, Ikeda S. Increased vulnerability to rotenone-induced neurotoxicity in ceruloplasmin-deficient mice. Neurosci Lett. 2008;446:56–8.CrossRef Kaneko K, Hineno A, Yoshida K, Ikeda S. Increased vulnerability to rotenone-induced neurotoxicity in ceruloplasmin-deficient mice. Neurosci Lett. 2008;446:56–8.CrossRef
19.
go back to reference Chang YZ, Qian ZM, Du JR, Zhu L, Xu Y, Li LZ, et al. Ceruloplasmin expression and its role in iron transport in c6 cells. Neurochem Int. 2007;50:726–33.CrossRef Chang YZ, Qian ZM, Du JR, Zhu L, Xu Y, Li LZ, et al. Ceruloplasmin expression and its role in iron transport in c6 cells. Neurochem Int. 2007;50:726–33.CrossRef
20.
go back to reference Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, David S. Ceruloplasmin regulates iron levels in the cns and prevents free radical injury. J Neurosci. 2002;22:6578–86.CrossRef Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, David S. Ceruloplasmin regulates iron levels in the cns and prevents free radical injury. J Neurosci. 2002;22:6578–86.CrossRef
21.
go back to reference Zanardi A, Conti A, Cremonesi M, D'Adamo P, Gilberti E, Apostoli P, et al. Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. EMBO Mol Med. 2018;10:91–106.CrossRef Zanardi A, Conti A, Cremonesi M, D'Adamo P, Gilberti E, Apostoli P, et al. Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. EMBO Mol Med. 2018;10:91–106.CrossRef
22.
go back to reference Patel BN, Dunn RJ, David S. Alternative rna splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. J Biol Chem. 2000;275:4305–10.CrossRef Patel BN, Dunn RJ, David S. Alternative rna splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. J Biol Chem. 2000;275:4305–10.CrossRef
23.
go back to reference Yang S, Hua Y, Nakamura T, Keep RF, Xi G. Upregulation of brain ceruloplasmin in thrombin preconditioning. Acta Neurochir Suppl. 2006;96:203–6.CrossRef Yang S, Hua Y, Nakamura T, Keep RF, Xi G. Upregulation of brain ceruloplasmin in thrombin preconditioning. Acta Neurochir Suppl. 2006;96:203–6.CrossRef
24.
go back to reference Zhao F, Xi G, Liu W, Keep RF, Hua Y. Minocycline attenuates iron-induced brain injury. Acta Neurochir Suppl. 2016;121:361–5.CrossRef Zhao F, Xi G, Liu W, Keep RF, Hua Y. Minocycline attenuates iron-induced brain injury. Acta Neurochir Suppl. 2016;121:361–5.CrossRef
25.
go back to reference Gaasch JA, Lockman PR, Geldenhuys WJ, Allen DD, Van der Schyf CJ. Brain iron toxicity: differential responses of astrocytes, neurons, and endothelial cells. Neurochem Res. 2007;32:1196–208.CrossRef Gaasch JA, Lockman PR, Geldenhuys WJ, Allen DD, Van der Schyf CJ. Brain iron toxicity: differential responses of astrocytes, neurons, and endothelial cells. Neurochem Res. 2007;32:1196–208.CrossRef
26.
go back to reference Welch KD, Davis TZ, Van Eden ME, Aust SD. Deleterious iron-mediated oxidation of biomolecules. Free Radic Biol Med. 2002;32:577–83.CrossRef Welch KD, Davis TZ, Van Eden ME, Aust SD. Deleterious iron-mediated oxidation of biomolecules. Free Radic Biol Med. 2002;32:577–83.CrossRef
27.
go back to reference Calabrese V, Lodi R, Tonon C, D'Agata V, Sapienza M, Scapagnini G, et al. Oxidative stress, mitochondrial dysfunction and cellular stress response in friedreich’s ataxia. J Neurol Sci. 2005;233:145–62.CrossRef Calabrese V, Lodi R, Tonon C, D'Agata V, Sapienza M, Scapagnini G, et al. Oxidative stress, mitochondrial dysfunction and cellular stress response in friedreich’s ataxia. J Neurol Sci. 2005;233:145–62.CrossRef
28.
go back to reference Shamoto-Nagai M, Maruyama W, Yi H, Akao Y, Tribl F, Gerlach M, et al. Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26s proteasome. J Neural Transm. 2006;113:633–44.CrossRef Shamoto-Nagai M, Maruyama W, Yi H, Akao Y, Tribl F, Gerlach M, et al. Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26s proteasome. J Neural Transm. 2006;113:633–44.CrossRef
29.
go back to reference Garton T, Keep RF, Hua Y, Xi G. Brain iron overload following intracranial haemorrhage. Stroke Vasc Neurol. 2016;1:172–84.CrossRef Garton T, Keep RF, Hua Y, Xi G. Brain iron overload following intracranial haemorrhage. Stroke Vasc Neurol. 2016;1:172–84.CrossRef
30.
go back to reference Karwacki Z, Kowianski P, Dziewatkowski J, Domaradzka-Pytel B, Ludkiewcz B, Wojcik S, et al. Apoptosis in the course of experimental intracerebral haemorrhage in the rat. Folia Morphol (Warsz). 2005;64:248–52. Karwacki Z, Kowianski P, Dziewatkowski J, Domaradzka-Pytel B, Ludkiewcz B, Wojcik S, et al. Apoptosis in the course of experimental intracerebral haemorrhage in the rat. Folia Morphol (Warsz). 2005;64:248–52.
31.
go back to reference David S, Patel BN. Ceruloplasmin: structure and function of an essential ferroxidase. Adv Struct Biol. 2000;6:211–37.CrossRef David S, Patel BN. Ceruloplasmin: structure and function of an essential ferroxidase. Adv Struct Biol. 2000;6:211–37.CrossRef
32.
go back to reference Zhao L, Hadziahmetovic M, Wang C, Xu X, Song Y, Jinnah HA, et al. Cp/heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem. 2015;135:958–74.CrossRef Zhao L, Hadziahmetovic M, Wang C, Xu X, Song Y, Jinnah HA, et al. Cp/heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem. 2015;135:958–74.CrossRef
33.
go back to reference Texel SJ, Zhang J, Camandola S, Unger EL, Taub DD, Koehler RC, et al. Ceruloplasmin deficiency reduces levels of iron and bdnf in the cortex and striatum of young mice and increases their vulnerability to stroke. PLoS One. 2011;6:e25077.CrossRef Texel SJ, Zhang J, Camandola S, Unger EL, Taub DD, Koehler RC, et al. Ceruloplasmin deficiency reduces levels of iron and bdnf in the cortex and striatum of young mice and increases their vulnerability to stroke. PLoS One. 2011;6:e25077.CrossRef
34.
go back to reference Shin EJ, Jeong JH, Chung CK, Kim DJ, Wie MB, Park ES, et al. Ceruloplasmin is an endogenous protectant against kainate neurotoxicity. Free Radic Biol Med. 2015;84:355–72.CrossRef Shin EJ, Jeong JH, Chung CK, Kim DJ, Wie MB, Park ES, et al. Ceruloplasmin is an endogenous protectant against kainate neurotoxicity. Free Radic Biol Med. 2015;84:355–72.CrossRef
Metadata
Title
Brain Ceruloplasmin Expression After Experimental Intracerebral Hemorrhage and Protection Against Iron-Induced Brain Injury
Authors
Hongwei Liu
Ya Hua
Richard F. Keep
Guohua Xi
Publication date
01-02-2019
Publisher
Springer US
Published in
Translational Stroke Research / Issue 1/2019
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-018-0669-0

Other articles of this Issue 1/2019

Translational Stroke Research 1/2019 Go to the issue