Clinical and Experimental Pediatrics

대한소아청소년과학회 (The Korean Pediatric Society)
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Neuroprotective effects of erythropoietin against hypoxic injury via modulation of the mitogen-activated protein kinase pathway and apoptosis

  • Jeong, Ji Eun (Department of Pediatrics, Daegu Catholic University Medical Center, Catholic University of Daegu School of Medicine) ;
  • Park, Jae Hyun (Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine) ;
  • Kim, Chun Soo (Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine) ;
  • Lee, Sang Lak (Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine) ;
  • Chung, Hai Lee (Department of Pediatrics, Daegu Catholic University Medical Center, Catholic University of Daegu School of Medicine) ;
  • Kim, Woo Taek (Department of Pediatrics, Daegu Catholic University Medical Center, Catholic University of Daegu School of Medicine) ;
  • Lee, Eun Joo (Department of Pediatrics, Kyungpook National University Hospital, Kyungpook National University School of Medicine)
  • 투고 : 2016.12.30
  • 심사 : 2017.04.11
  • 발행 : 2017.06.15
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Purpose: Hypoxic-ischemic encephalopathy is a significant cause of neonatal morbidity and mortality. Erythropoietin (EPO) is emerging as a therapeutic candidate for neuroprotection. Therefore, this study was designed to determine the neuroprotective role of recombinant human EPO (rHuEPO) and the possible mechanisms by which mitogen-activated protein kinase (MAPK) signaling pathway including extracellular signal-regulated kinase (ERK1/2), JNK, and p38 MAPK is modulated in cultured cortical neuronal cells and astrocytes. Methods: Primary neuronal cells and astrocytes were prepared from cortices of ICR mouse embryos and divided into the normoxic, hypoxia (H), and hypoxia-pretreated with EPO (H+EPO) groups. The phosphorylation of MAPK pathway was quantified using western blot, and the apoptosis was assessed by caspase-3 measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results: All MAPK pathway signals were activated by hypoxia in the neuronal cells and astrocytes (P<0.05). In the neuronal cells, phosphorylation of ERK-1/-2 and apoptosis were significantly decreased in the H+EPO group at 15 hours after hypoxia (P<0.05). In the astrocytes, phosphorylation of ERK-1/-2, p38 MAPK, and apoptosis was reduced in the H+EPO group at 15 hours after hypoxia (P<0.05). Conclusion: Pretreatment with rHuEPO exerts neuroprotective effects against hypoxic injury reducing apoptosis by caspase-dependent mechanisms. Pathologic, persistent ERK activation after hypoxic injury may be attenuateed by pretreatment with EPO supporting that EPO may regulate apoptosis by affecting ERK pathways.

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참고문헌

  1. Han BH, Holtzman DM. BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci 2000;20:5775-81. https://doi.org/10.1523/JNEUROSCI.20-15-05775.2000
  2. Johnston MV, Fatemi A, Wilson MA, Northington F. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011;10:372-82. https://doi.org/10.1016/S1474-4422(11)70016-3
  3. Volpe JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 2001;7:56-64. https://doi.org/10.1002/1098-2779(200102)7:1<56::AID-MRDD1008>3.0.CO;2-A
  4. Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol 2005;15:234-40.
  5. Lombardero M, Kovacs K, Scheithauer BW. Erythropoietin: a hormone with multiple functions. Pathobiology 2011;78:41-53. https://doi.org/10.1159/000322975
  6. Rangarajan V, Juul SE. Erythropoietin: emerging role of erythropoietin in neonatal neuroprotection. Pediatr Neurol 2014;51:481-8. https://doi.org/10.1016/j.pediatrneurol.2014.06.008
  7. Rabie T, Marti HH. Brain protection by erythropoietin: a manifold task. Physiology (Bethesda) 2008;23:263-74.
  8. Rafiee P, Shi Y, Su J, Pritchard KA Jr, Tweddell JS, Baker JE. Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic Res Cardiol 2005;100:187-97. https://doi.org/10.1007/s00395-004-0508-1
  9. Almaguer-Melian W, Merceron-Martinez D, Pavon-Fuentes N, Alberti-Amador E, Leon-Martinez R, Ledon N, et al. Erythropoietin promotes neural plasticity and spatial memory recovery in fimbria-fornix-lesioned rats. Neurorehabil Neural Repair 2015;29:979-88. https://doi.org/10.1177/1545968315572389
  10. Buemi M, Cavallaro E, Floccari F, Sturiale A, Aloisi C, Trimarchi M, et al. Erythropoietin and the brain: from neurodevelopment to neuroprotection. Clin Sci (Lond) 2002;103:275-82. https://doi.org/10.1042/cs1030275
  11. Chin K, Yu X, Beleslin-Cokic B, Liu C, Shen K, Mohrenweiser HW, et al. Production and processing of erythropoietin receptor transcripts in brain. Brain Res Mol Brain Res 2000;81:29-42. https://doi.org/10.1016/S0169-328X(00)00157-1
  12. Bernaudin M, Bellail A, Marti HH, Yvon A, Vivien D, Duchatelle I, et al. Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia 2000;30:271-8. https://doi.org/10.1002/(SICI)1098-1136(200005)30:3<271::AID-GLIA6>3.0.CO;2-H
  13. Ma C, Cheng F, Wang X, Zhai C, Yue W, Lian Y, et al. Erythropoietin pathway: a potential target for the treatment of depression. Int J Mol Sci 2016;17(5). https://doi.org/10.3390/ijms17050677.
  14. Alnaeeli M, Wang L, Piknova B, Rogers H, Li X, Noguchi CT. Erythropoietin in brain development and beyond. Anat Res Int 2012;2012:953264.
  15. Miljus N, Heibeck S, Jarrar M, Micke M, Ostrowski D, Ehrenreich H, et al. Erythropoietin-mediated protection of insect brain neurons involves JAK and STAT but not PI3K transduction pathways. Neuroscience 2014;258:218-27. https://doi.org/10.1016/j.neuroscience.2013.11.020
  16. Walker CL, Liu NK, Xu XM. PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries. Front Biol (Beijing) 2013;8(4). https://doi.org/10.1007/s11515-013-1255-1.
  17. Nito C, Kamada H, Endo H, Narasimhan P, Lee YS, Chan PH. Involvement of mitogen-activated protein kinase pathways in expression of the water channel protein aquaporin-4 after ischemia in rat cortical astrocytes. J Neurotrauma 2012;29:2404-12. https://doi.org/10.1089/neu.2012.2430
  18. Lan A, Liao X, Mo L, Yang C, Yang Z, Wang X, et al. Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells. PLoS One 2011;6:e25921. https://doi.org/10.1371/journal.pone.0025921
  19. Chen L, Liu L, Yin J, Luo Y, Huang S. Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. Int J Biochem Cell Biol 2009;41:1284-95. https://doi.org/10.1016/j.biocel.2008.10.029
  20. Ferrer I, Friguls B, Dalfo E, Planas AM. Early modifications in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia. Acta Neuropathol 2003;105:425-37.
  21. Kim BC, Kim MK, Cho KH, Kim YS, Lee KY. Activation of mitogenactivated protein kinases in hypoxia-induced apoptosis of PC12 cell. J Korean Neurol Assoc 2001;19:384-92.
  22. Lesuisse C, Martin LJ. Long-term culture of mouse cortical neurons as a model for neuronal development, aging, and death. J Neurobiol 2002;51:9-23. https://doi.org/10.1002/neu.10037
  23. Schildge S, Bohrer C, Beck K, Schachtrup C. Isolation and culture of mouse cortical astrocytes. J Vis Exp 2013;(71). pii: 50079. https://doi.org/10.3791/50079.
  24. Tang Z, Sun X, Huo G, Xie Y, Shi Q, Chen S, et al. Protective effects of erythropoietin on astrocytic swelling after oxygen-glucose deprivation and reoxygenation: mediation through AQP4 expression and MAPK pathway. Neuropharmacology 2013;67:8-15. https://doi.org/10.1016/j.neuropharm.2012.10.017
  25. Kwon MS, Kim MH, Kim SH, Park KD, Yoo SH, Oh IU, et al. Erythropoietin exerts cell protective effect by activating PI3K/Akt and MAPK pathways in C6 Cells. Neurol Res 2014;36:215-23. https://doi.org/10.1179/1743132813Y.0000000284
  26. Thomas GM, Huganir RL. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 2004;5:173-83. https://doi.org/10.1038/nrn1346
  27. Jones NM, Bergeron M. Hypoxia-induced ischemic tolerance in neonatal rat brain involves enhanced ERK1/2 signaling. J Neurochem 2004;89:157-67. https://doi.org/10.1111/j.1471-4159.2004.02324.x
  28. Lee E, Choi SY, Yang JH, Lee YJ. Preventive effects of imperatorin on perfluorohexanesulfonate-induced neuronal apoptosis via inhibition of intracellular calcium-mediated ERK pathway. Korean J Physiol Pharmacol 2016;20:399-406. https://doi.org/10.4196/kjpp.2016.20.4.399
  29. Subramaniam S, Zirrgiebel U, von Bohlen Und Halbach O, Strelau J, Laliberte C, Kaplan DR, et al. ERK activation promotes neuronal degeneration predominantly through plasma membrane damage and independently of caspase-3. J Cell Biol 2004;165:357-69. https://doi.org/10.1083/jcb.200403028
  30. Kilic E, Kilic U, Soliz J, Bassetti CL, Gassmann M, Hermann DM. Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways. FASEB J 2005;19:2026-8. https://doi.org/10.1096/fj.05-3941fje
  31. Yuan QC, Jiang L, Zhu LH, Yu DF. Impacts of erythropoietin on vascular endothelial growth factor receptor 2 by the extracellular signal-regulated kinase signaling pathway in a neonatal rat model of periventricular white matter damage. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2016;38:217-21.
  32. Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, et al. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci 2002;22:10291-301. https://doi.org/10.1523/JNEUROSCI.22-23-10291.2002

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  5. The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization vol.22, pp.14, 2017, https://doi.org/10.3390/ijms22147682