<strong>Hepcidin and Iron-associated Neurodegenerative Disorders</strong>

Abstract

Abstract:The abnormally increased iron in the brain is an initial cause of neuronal death at least in some neurodegenerative. By binding to a unique cellular iron exporter，ferroportin 1 result in its endocytosis and degradation，and inhibit the release of duodenal iron to plasma and inhibit the release of iron from macrophage，then regulat the iron homeostasis of the body. Therefore，hepcidin is a new target for pharmacological intervention in these diseases. Reducing iron to normal level or hampering iron to increase with age in the brain is a promising therapeutic strategy for all iron-associated neurodegenerative disorders. Recent studies demonstrated that increasing hepcidin level in the brain could significantly reduce brain iron contents by regulating the expression of iron transport proteins located in the brain-blood barrier （BBB），neurons and astrocytes. This review mainly discusses the role of hepcidin in the brain and its potential therapeutic role in the disease，providing a new strategy for the prevention and treatment of those diseases.

Key words:brain iron metabolism,neurodegenerative disorders,hepcidin

CLC Number:

R964

MA Juan，ZHANG Fa-li，QIAN Zhong-ming.Hepcidin and Iron-associated Neurodegenerative Disorders[J]. Acta Neuropharmacologica, 2018, 8(1): 16-22.

References

[1] Alexander Krause, Susanne Neitz, Hans-Jurgen Magert, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity[J]. FEBS Lett, 2000, 480(2-3):147-150.

[2] Christina H Park, Erika V Valore, Alan J Waring, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver[J]. J Biol Chem, 2001, 276(11):7806-7810.

[3] Christelle Pigeon, Gennady Ilyin, Brice Courselaud, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload[J]. J Biol Chem, 2001, 276(11):7811-7819.

[4] Eileen Fung, Elizabeta Nemeth. Manipulation of the hepcidin pathway for therapeutic purposes[J]. Haematologica, 2013, 98(11):1667-1676.

[5] Pitotr Ruchala, Elizabeta Nemeth. The pathophysiology and pharmacology of hepcidin[J]. Trends Pharmacol Sci, 2014, 35(3):155-161.

[6] Tomas Ganz. Systemic iron homeostasis[J]. Physiol Rev, 2013, 93(4):1721-1741.

[7] Maura Poli, Michela Asperti, Paola Ruzzenenti, et al. Hepcidin antagonists for potential treatments of disorders with hepcidin excess[J]. Front Pharmacol, 2014, 5:86.

[8] Dominic J Hare, Barbara Rita Cardoso, Erika P Raven, et al. Excessive early-life dietary exposure: a potential source of elevated brain iron and a risk factor for Parkinson’s disease[J]. NPJ Parkinson's Disease, 2017, 3:1.

[9] Mark A Smith, Peggy L R Harris, Lawrence M Sayre, et al. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals[J]. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94(18):9866-9868.

[10] Kiersten L Berggren, Chen Jian-fang, Julia Fox, et al. Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease[J]. Redox Biology, 2015, 4:363-374.

[11] Antonello Pietrangelo. Hepcidin in human iron disorders: therapeutic implications[J]. J Hepatol, 2011, 54(1):173-181.

[12] Arezes J, Nemeth E. Hepcidin and iron disorders: new biology and clinical approaches[J]. Int J Lab Hematol, 2015, 37(Suppl 1):92-98.

[13] Lisa Lombardi, Giuseppantonio Maisetta, Giovanna Batoni, et al. Insights into the antimicrobial properties of hepcidins: advantages and drawbacks as potential therapeutic agents[J]. Molecules, 2015, 20(4):6319-6341.

[14] Luc Rochette, Aurelie Gudjoncik, Charles Guenancia, et al. The iron-regulatory hormone hepcidin: a possible therapeutic target?[J]. Pharmacol Ther, 2015, 146:35-52.

[15] Liu Jing, Sun Bing-bing, Yin Hui-jun, et al. Hepcidin: a promising therapeutic target for iron disorders: a systematic review[J]. Medicine (Baltimore), 2016, 95(14):e3150.

[16] Nicole L Blanchette, David H Manz, Frank M Torti, et al. Modulation of hepcidin to treat iron deregulation: potential clinical applications[J]. Expert Rev Hematol, 2016, 9(2):169-186.

[17] Karin E Finberg. Regulation of systemic iron homeostasis[J]. Curr Opin Hematol, 2013, 20(3):208-214.

[18] Alfons Lawen, Darius Lane. Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action[J]. Antioxid Redox Signal, 2013, 18(18):2473-2507.

[19] Delphine Meynard, Jodie L Babitt, Herbert Y Lin. The liver: conductor of systemic iron balance[J]. Blood, 2014, 123(2):168-176.

[20] Hal Drakesmith, Elizabeta Nemeth, Tomas Ganz. Ironing out Ferroportin[J]. Cell Metab, 2015, 22(5):777-787.

[21] Bruno Silva, Paula Faustino. An overview of molecular basis of iron metabolism regulation and the associated pathologies[J]. Biochim Biophys Acta, 2015, 1852(7):1347-1359.

[22] Pierre Brissot, Olivier Loreal. Iron metabolism and related genetic diseases: A cleared land, keeping mysteries[J]. J Hepatol, 2016, 64(2):505-515.

[23] Raffaella Gozzelino, Paolo Arosio. Iron homeostasis in health and disease[J]. Int J Mol Sci, 2016, 17(1):130.

[24] Pietrangelo A. Iron and the liver[J]. Liver Int, 2016, 36(Suppl 1):116-123.

[25] Rosa Maria Pellegrino, Enrica Boda, Francesca Montarolo, et al. Transferrin receptor 2 dependent alterations of brain iron metabolism affect anxiety circuits in the mouse[J]. Sci Rep, 2016, 6:30725.

[26] Zechel S, Huber-Wittmer K, von Bohlen und Halbach O. Distribution of the iron-regulating protein hepcidin in the murine central nervous system[J]. J Neurosci Res, 2006, 84(4):790-800.

[27] Wang Qin, Du Fang, Qian Zhong-ming, et al. Lipopolysaccharide induces a significant increase in expression of iron regulatory hormone hepcidin in the cortex and substantia nigra in rat brain[J]. Endocrinology, 2008, 149(8):3920-3925.

[28] Lu L N, Qian Z M, Wu K C, et al. Expression of iron transporters and pathological hallmarks of parkinson's and alzheimer's diseases in the brain of young, adult, and aged rats[J]. Mol Neurobiol, 2017, 54(7):5213-5224.

[29] Wang S M, Fu L J, Duan X L, et al. Role of hepcidin in murine brain iron metabolism[J]. Cell Mol Life Sci, 2010, 67(1):123-133.

[30] Ruma Raha-Chowdhury, Animesh Alexander Raha, Serhiy Forostyak, et al. Expression and cellular localization of hepcidin mRNA and protein in normal rat brain[J]. BMC Neurosci, 2015, 16:24.

[31] Stacey L Clardy, Wang Xin-sheng, Philip J Boyer, et al. Is ferroportin-hepcidin signaling altered in restless legs syndrome?[J]. J Neurol Sci, 2006, 247(2):173-179.

[32] Milla M Hanninen, Joonas Haapasalo, Hannu Haapasalo, et al. Expression of iron-related genes in human brain and brain tumors[J]. BMC Neurosci, 2009, 10:36.

[33] Animesh Alexander Raha, Radhika Anand Vaishnav, Robert Paul Friedland, et al. The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease[J]. Acta Neuropathol Commun, 2013, 1:55.

[34] Elizabeta Nemeth, Erika V Valore, Mary Territo, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein[J]. Blood, 2003, 101(7):2461-2463.

[35] Gael Nicolas, Caroline Chauvet, Lydie Viatte, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation[J]. J Clin Invest, 2002, 110(7):1037-1044.

[36] Hiroko Shike, Xavier Lauth, Mark E Westerman, et al. Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge[J]. Eur J Biochem, 2002, 269(8):2232-2237.

[37] David A Weinstein, Cindy N Roy, Mark D Fleming, et al. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease[J]. Blood, 2002, 100(10):3776-3781.

[38] Nermi L Parrow, Robert E Fleming. Bone morphogenetic proteins as regulators of iron metabolism[J]. Annu Rev Nutr, 2014, 34:77-94.

[39] Paul J Schmidt. Regulation of iron metabolism by hepcidin under conditions of inflammation[J]. J Biol Chem, 2015, 290(31):18975-18983.

[40] Li Xiang, David K Rhee, Rajeev Malhotra, et al. Progesterone receptor membrane component-1 regulates hepcidin biosynthesis[J]. J Clin Invest, 2016, 126(1):389-401.

[41] Marques F, Falcao A M, Sousa J C, et al. Altered iron metabolism is part of the choroid plexus response to peripheral inflammation[J]. Endocrinology, 2009, 150(6):2822-2828.

[42] Pamela Urrutia, Pabla Aguirre, Andres Esparza, et al. Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells[J]. J Neurochem, 2013, 126(4):541-549.

[43] Jacqueline C Lieblein-Boff, Daniel B McKim, Daniel T Shea, et al. Neonatal E. coli infection causes neuro-behavioral deficits associated with hypomyelination and neuronal sequestration of iron[J]. J Neurosci, 2013, 33(41):16334-16345.

[44] Ihtzaz Ahmed Malik, Naila Naz, Nadeem Sheikh, et al. Comparison of changes in gene expression of transferrin receptor-1 and other iron-regulatory proteins in rat liver and brain during acute-phase response[J]. Cell Tissue Res, 2011, 344(2):299-312.

[45] Ding Hui, Yan Cai-zhen, Shi Hong-lian, et al. Hepcidin is involved in iron regulation in the ischemic brain[J]. PLoS One, 2011, 6(9):e25324.

[46] Qian Zhong-ming, He Xuan, Liang Tuo, et al. Lipopolysaccharides upregulate hepcidin in neuron via microglia and the IL-6/STAT3 signaling pathway[J]. Mol Neurobiol, 2014, 50(3):811-820.

[47] Liu Chong-bin, Wang Rui, Dong Miao-wu, et al. Expression of hepcidin at the choroid plexus in normal aging rats is associated with IL-6/Stat3 signaling pathway[J]. Sheng Li Xue Bao, 2014, 66(6):639-646.

[48] Du Fang, Chrisopher Qian, Qian Zhong-ming, et al. Hepcidin directly inhibits transferrin receptor 1 expression in astrocytes via a cyclic AMP-protein kinase A pathway[J]. Glia, 2011, 59(6):936-945.

[49] Du Fang, Qian Zhong-ming, Luo Qian-qian, et al. Hepcidin suppresses brain iron accumulation by downregulating iron transport proteins in iron-overloaded rats[J]. Mol Neurobiol, 2015, 52(1):101-114.

[50] Silverthorn DU. Introduction to the endocrine system [M]. Human physiology, 4rd ed. San Francisco: Benjamin Cummings, 2009, chapter 7.

[51] W Page Faulk, Bae-Li Hsi, P J Stevens. Transferrin and transferrin receptors in carcinoma of the breast[J]. Lancet, 1980, 2(8191):390-392.

[52] Trowbridge I S, Omary M B. Human cell surface glycoprotein related to cell proliferation is the receptor for transferrin[J]. Proc Natl Acad Sci USA, 1981, 78(5):3039-3043.

[53] Li Hong-yan, Sun Hong-zhe, Qian Zhong-ming. The role of the transferrin-transferrin-receptor system in drug delivery and targeting[J]. Trends Pharmacol Sci, 2002, 23(5):206-209.

[54] Li Hong-yan, Qian Zhong-ming. Transferrin/transferrin receptor-mediated drug delivery[J]. Med Res Rev, 2002, 22(3):225-250.

[55] Tracy R Daniels, Tracie Delgado, Gustavo Helguera, et al. The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells[J]. Clin Immunol, 2006, 121(2):159-176.

[56] Yorka Munoz, Carlos Mauricio Carrasco, Joaquin D Campos, et al. Parkinson's disease: the mitochondria-iron link[J]. Parkinsons Dis, 2016, 2016:7049108.

[57] Ke Ya, Qian Zhong-ming. Iron misregulation in the brain: a primary cause of neurodegenerative disorders[J]. Lancet Neurol, 2003, 2(4):246-253.

[58] Ke Ya, Qian Zhong-ming. Brain iron metabolism: neurobiology and neurochemistry[J]. Prog Neurobiol, 2007, 83(3):149-173.

[59] Orly Weinreb, Silvia Mandel, Moussa B H Youdim, et al. Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators[J]. Free Radic Biol Med, 2013, 62:52-64.

[60] Guillaume Grolez, Caroline Moreau, Bernard Sablonniere, et al. Ceruloplasmin activity and iron chelation treatment of patients with Parkinson's disease[J]. BMC Neurol, 2015, 15:74.

[61] Adbel Ali Belaidi, Ashley I Bush. Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics[J]. J Neurochem, 2016, 139(Suppl 1):179-197.

[62] Petr Dusek, Susanne A Schneider, Jan Aaseth. Iron chelation in the treatment of neurodegenerative diseases[J]. J Trace Elem Med Biol, 2016, 38:81-92.

[63] Chang Yan-zhong, Qian Zhong-ming, Wang Kui, et al. Effects of development and iron status on ceruloplasmin expression in rat brain[J]. J Cell Physiol, 2005, 204(2):623-631.

[64] Ke Ya, Chang Yan-zhong, Duan Xiang-lin, et al. Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain[J]. Neurobiol Aging, 2005, 26(5):739-748.

[65] Gong Jing, Du Fang, Qian Zhong-ming, et al. Pre-treatment of rats with ad-hepcidin prevents iron-induced oxidative stress in the brain[J]. Free Radic Biol Med, 2016, 90:126-132.

[66] Seth Rivera, Liu Lide, Elizabeta Nemeth, et al. Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia[J]. Blood, 2005, 105(4):1797-1802.

[67] Christopher D Fjell, Jan A Hiss, Robert E W Hancock, et al. Designing antimicrobial peptides: form follows function[J]. Nat Rev Drug Discov, 2011, 11(1):37-51.

[68] Gloria Cuevas Preza, Pitor Ruchala, Rogelio Pinon, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload[J]. J Clin Invest, 2011, 121(12):4880-4888.

[69] Luo Xiao, Jiang Qian, Song Ge, et al. Efficient oxidative folding and site-specific labeling of human hepcidin to study its interaction with receptor ferroportin[J]. Febs J, 2012, 279(17):3166-3175.

[70] Song Ge, Jiang Qian, Xu Ting, et al. A convenient luminescence assay of ferroportin internalization to study its interaction with hepcidin[J]. Febs J, 2013, 280(8):1773-1781.

[71] Lisa K Ryan, Katie B Freeman, Jorge A Masso-Silva, et al. Activity of potent and selective host defense peptide mimetics in mouse models of oral candidiasis[J]. Antimicrob Agents Chemother, 2014, 58(7):3820-3827.

Hepcidin and Iron-associated Neurodegenerative Disorders

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles15

Recommended Articles

Metrics

[1]	SUN Yi，TAN Bo，SU Rui-bin.Biased Ligand——Novel Paradigm for Opioid Analgesics[J]. Acta Neuropharmacologica, 2018, 8(2): 1-7.
[2]	WANG Jin-hui，HUANG Li，CHEN Na.Ischemic Injury of Cortical GABAergic Neurons：Vulnerability，Mechanism and Pathological Impacts[J]. Acta Neuropharmacologica, 2018, 8(2): 8-25.
[3]	DU Guan-hua，ZHANG Wen，DU Li-da，MA Yin-zhong，LI Li，WANG Yue-hua.New Strategies for the Drug Development of Anti-cerebral Ischemia —Advances in the Etiology and Drug Development of Acute Cerebral Ischemia[J]. Acta Neuropharmacologica, 2018, 8(1): 1-8.
[4]	LIN Zhi-bin.Pharmacological Progress of Ganoderma on Anti-aging and Anti-Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2018, 8(1): 9-15.
[5]	YANG Yan-fei，HUANG Zhi-li.Recent Advance on Sleep-Wake Regulation Based on Novel Techniques for Specific Manipulations of Neuron Activities[J]. Acta Neuropharmacologica, 2018, 8(1): 23-34.
[6]	WANG Yun，ZHEN Xue-chu.An Update on Allosteric Modulator of Sigma-1 Receptors: Potential Applications[J]. Acta Neuropharmacologica, 2018, 8(1): 35-44.
[7]	ZAN Gui-ying，SUN Xiang，LI Qing-lin，LIU Jing-gen.Research Progress of the Role and Underlying Mechanism of Dynorphin/κ Opioid Receptor in the Development of Depression[J]. Acta Neuropharmacologica, 2018, 8(1): 54-64.
[8]	ZHANG Kuo，YANG Jing-yu，WU Chun-fu.Progress on Pathophysiology and Animal Models of Depression[J]. Acta Neuropharmacologica, 2017, 7(4): 8-16.
[9]	REN Jing，ZHANG Dan-shen.Progress in Research of Brain Targeting Ligand for Nano-scale Drug Delivery Systems[J]. Acta Neuropharmacologica, 2017, 7(4): 17-25.
[10]	PANG Xue-bo，XUE Qian，ZOU Yu-an.The Research Progress of Plasma Lipoprotein-associated Phospholipase A2 and Ischemic Stroke[J]. Acta Neuropharmacologica, 2017, 7(4): 31-35.
[11]	WAN Ye，GUO Chun-yan，LI Yong-min.Research Progress of Traditional Chinese Medicine in Parkinson’s Disease[J]. Acta Neuropharmacologica, 2017, 7(4): 36-42.
[12]	WANG Cui, GUO Tong-lin, SHEN Li-xia.Study on the Neuroprotective Effects of Phytoestrogens in Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2017, 7(4): 43-52.
[13]	BAI Yan-chang，JIA Yan-li，SONG Ya-xue，WANG Jian-hua.Advance of Functional Magnetic Resonance Imaging of Brain in Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2017, 7(3): 6-11.
[14]	REN Qian,WANG Zhen-zhen,CHEN Nai-hong.Regulation of Neuroplasticity by MicroRNA in Depression Disorder[J]. Acta Neuropharmacologica, 2017, 7(3): 12-20.
[15]	HUANG Qian，SUN Ming-li，LI Teng-fei，WANG Yong-xiang.Research Progress on Mechanisms Underlying Aconitines Analgesia[J]. Acta Neuropharmacologica, 2017, 7(3): 21-32.