Abstract
Erythropoietin is a cytokine that binds to the Erythropoietin receptor and regulates the formation of erythroid cells during erythropoiesis in the bone marrow. However, many other organs and tissues express Erythropoietin and its receptor, such as the Nervous System, which principally regulates tissue protection. In the Central Nervous System, Erythropoietin is principally expressed by astrocytes, while neurons mainly express Erythropoietin receptors. Moreover, Erythropoietin acts as a pleiotropic molecule with neuroprotective effects, and its mechanisms of signal transduction pathways are defined, and there is a growing interest in its therapeutic potential. This review focuses on the role of Erythropoietin and its relationship with HIF1, PI3/Akt, GSK3B, JAK/STAT, and MAPKs signaling pathways that leads to cell survival after injury in the Central Nervous System. Knowledge of these signaling systems comprehensively could better guide EPO treatment to restoring different SNC alterations mediated by different insults.
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References
Acker T, Acker H (2004) Cellular oxygen sensing need in CNS function: physiological and pathological implications. J Exp Biol 207(Pt 18):3171–3188. https://doi.org/10.1242/jeb.01075
Arcasoy MO (2008) The non-haematopoietic biological effects of erythropoietin. Br J Haematol 141(1):14–31. https://doi.org/10.1111/j.1365-2141.2008.07014.x
Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G (2001) Chemokines and their receptors in the central nervous system. Front Neuroendocrinol 22(3):147–184. https://doi.org/10.1006/frne.2001.0214
Barbero S, Bajetto A, Bonavia R, Porcile C, Piccioli P, Pirani P, Ravetti JL, Zona G, Spaziante R, Florio T, Schettini G (2002) Expression of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1 in human brain tumors and their involvement in glial proliferation in vitro. Ann N Y Acad Sci 973:60–69. https://doi.org/10.1111/j.1749-6632.2002.tb04607.x
Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19(6):643–651. https://doi.org/10.1097/00004647-199906000-00007
Bernaudin M, Bellail A, Marti HH, Yvon A, Vivien D, Duchatelle I, Mackenzie ET, Petit E (2000) Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia 30(3):271–278
Bittorf T, Büchse T, Sasse T, Jaster R, Brock J (2001) Activation of the transcription factor NF-kappaB by the erythropoietin receptor: structural requirements and biological significance. Cell Signal 13(9):673–681. https://doi.org/10.1016/s0898-6568(01)00189-9
Burotto M, Chiou VL, Lee JM, Kohn EC (2014) The MAPK pathway across different malignancies: a new perspective. Cancer 120(22):3446–3456. https://doi.org/10.1002/cncr.28864
Castañeda-Arellano R, Feria-Velasco AI, Rivera-Cervantes MC (2014) Activity increase in EpoR and Epo expression by intra-nasal recombinant human erythropoietin (rhEpo) administration in ischemic hippocampi of adult rats. Neurosci Lett 583:16–20. https://doi.org/10.1016/j.neulet.2014.09.013
Chen RL, Ogunshola OO, Yeoh KK, Jani A, Papadakis M, Nagel S, Schofield CJ, Buchan AM (2014) HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice. J Neurochem 131(2):177–189. https://doi.org/10.1111/jnc.12804
Cheng MF, Chen LJ, Niu HS, Yang TT, Lin KC, Cheng JT (2015) Signals mediating Klotho-induced neuroprotection in hippocampal neuronal cells. Acta Neurobiol Exp (wars) 75(1):60–71
Chikuma M, Masuda S, Kobayashi T, Nagao M, Sasaki R (2000) Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus. Am J Physiol Endocrinol Metab 279(6):E1242–E1248. https://doi.org/10.1152/ajpendo.2000.279.6.E1242
Chin K, Yu X, Beleslin-Cokic B, Liu C, Shen K, Mohrenweiser HW, Noguchi CT (2000) Production and processing of erythropoietin receptor transcripts in brain. Brain Res Mol Brain Res 81(1–2):29–42. https://doi.org/10.1016/s0169-328x(00)00157-1
Chong ZZ, Maiese K (2007) Erythropoietin involves the phosphatidylinositol 3-kinase pathway, 14–3-3 protein and FOXO3a nuclear trafficking to preserve endothelial cell integrity. Br J Pharmacol 150(7):839–850. https://doi.org/10.1038/sj.bjp.0707161 (Epub 2007 Mar 5)
Chong ZZ, Lin SH, Kang JQ, Maiese K (2003) Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspase 1, 3, and 8. J Neurosci Res 71(5):659–669. https://doi.org/10.1002/jnr.10528
Chong ZZ, Lin SH, Li F, Maiese K (2005) The sirtuin inhibitor nicotinamide enhances neuronal cell survival during acute anoxic injury through Akt, Bad, PARP, and mitochondrial associated “antiapoptotic” pathways. Curr Neurovasc Res 2(4):271–285. https://doi.org/10.2174/156720205774322584
Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: The PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6:184–192. https://doi.org/10.1038/nrc1819
Deveraux QL, Reed JC (1999) IAP family proteins, suppressors of apoptosis. Genes Dev 13:239–252. https://doi.org/10.1101/gad.13.3.239
Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412(6847):641–647. https://doi.org/10.1038/35088074
Diomede F, Zingariello M, Cavalcanti MFXB, Merciaro I, Pizzicannella J, De Isla N, Caputi S, Ballerini P, Trubiani O (2017) MyD88/ERK/NFkB pathways and pro-inflammatory cytokines release in periodontal ligament stem cells stimulated by Porphyromonas gingivalis. Eur J Histochem 61(2):2791. https://doi.org/10.4081/ejh.2017.2791
Fuse Y, Nakajima H, Nakajima-Takagi Y, Nakajima O, Kobayashi M (2015) Heme-mediated inhibition of Bach1 regulates the liver specificity and transience of the Nrf2-dependent induction of zebrafish heme oxygenase 1. Genes Cells 20(7):590–600. https://doi.org/10.1111/gtc.12249
Grimm C, Wenzel A, Groszer M, Mayser H, Seeliger M, Samardzija M, Bauer C, Gassmann M, Remé CE (2002) HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 8(7):718–724. https://doi.org/10.1038/nm723
Gross A, McDonnell JM, Korsmeyer SJ (1999) Bcl-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911. https://doi.org/10.1101/gad.13.15.1899
Hemani S, Lane O, Agarwal S, Yu SP, Woodbury A (2021) Systematic review of erythropoietin (EPO) for neuroprotection in human studies. Neurochem Res 46(4):732–739. https://doi.org/10.1007/s11064-021-03242-z
Hou J, Wang S, Shang YC, Chong ZZ, Maiese K (2011) Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress. Curr Neurovasc Res 8(3):220–235. https://doi.org/10.2174/156720211796558069
Hou Y, Wang K, Wan W, Cheng Y, Pu X, Ye X (2018) Resveratrol provides neuroprotection by regulating the JAK2/STAT3/PI3K/AKT/mTOR pathway after stroke in rats. Genes Dis 5(3):245–255. https://doi.org/10.1016/j.gendis.2018.06.001
Jin X, Wei Y, Xu F, Zhao M, Dai K, Shen R, Yang S, Zhang N (2018) SIRT1 promotes formation of breast cancer through modulating Akt activity. J Cancer 9(11):2012–2023. https://doi.org/10.7150/jca.24275
Kasof GM, Gomes BC (2001) Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem 276(5):3238–3246. https://doi.org/10.1074/jbc.M003670200
Kletkiewicz H, Hyjek M, Jaworski K, Nowakowska A, Rogalska J (2018) Activation of hypoxia-inducible factor-1α in rat brain after perinatal anoxia: role of body temperature. Int J Hyperthermia 34(6):824–833. https://doi.org/10.1080/02656736.2017.1385860
Kong F, Sun Y, Song W, Zhou Y, Zhu S (2020) MiR-216a alleviates LPS-induced acute lung injury via regulating JAK2/STAT3 and NF-κB signaling. Hum Cell 33(1):67–78. https://doi.org/10.1007/s13577-019-00289-7 (Epub 2019 Nov 29)
Krantic S, Mechawar N, Reix S, Quirion R (2007) Apoptosis-inducing factor: a matter of neuron life and death. Prog Neurobiol 81(3):179–196. https://doi.org/10.1016/j.pneurobio.2006.12.002
Kretz A et al (2004) Excess Bcl-XL increases the intrinsic growth potential of adult CNS neurons in vitro. Mol Cell Neurosci 26(1):63–74
Kretz A, Happold CJ, Marticke JK, Isenmann S (2005) Erythropoietin promotes regeneration of adult CNS neurons via Jak2/Stat3 and PI3K/AKT pathway activation. Mol Cell Neurosci 29(4):569–579. https://doi.org/10.1016/j.mcn.2005.04.009
Kuhrt D, Wojchowski DM (2015) Emerging EPO and EPO receptor regulators and signal transducers. Blood 125(23):3536–3541. https://doi.org/10.1182/blood-2014-11-575357
Lagarto A, Bueno V, Sanchez JA et al (2012) Short-term intra-nasal erythropoietin administration with low sialic acid content is without toxicity or erythropoietic effects. Curr Neurovasc Res 9(4):233–238. https://doi.org/10.2174/156720212803530645
Lee SM, Nguyen TH, Park MH, Kim KS, Cho KJ, Moon DC, Kim HY, Yoon DY, Hong JT (2004) EPO receptor-mediated ERK kinase and NF-kappaB activation in erythropoietin-promoted differentiation of astrocytes. Biochem Biophys Res Commun 320(4):1087–1095. https://doi.org/10.1016/j.bbrc.2004.06.060
Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll DM, Yu H (2009) Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 15(4):283–293. https://doi.org/10.1016/j.ccr.2009.02.015
Li Y, Schlamp CL, Poulsen KP, Nickells RW (2000) Bax-dependent and independent pathways of retinal ganglion cell death induced by different damaging stimuli. Exp Eye Res 71(2):209–213. https://doi.org/10.1006/exer.2000.0873
Li X, Chen Y, Shao S, Tang Q, Chen W, Chen Y, Xu X (2016) Oxidative stress induces the decline of brain EPO expression in aging rats. Exp Gerontol 83:89–93. https://doi.org/10.1016/j.exger.2016.07.012
Li R, Zhang LM, Sun WB (2017) Erythropoietin rescues primary rat cortical neurons from pyroptosis and apoptosis via Erk1/2-Nrf2/Bach1 signal pathway. Brain Res Bull 130:236–244. https://doi.org/10.1016/j.brainresbull.2017.01.016
Liu R, Suzuki A, Guo Z, Mizuno Y, Urabe T (2006) Intrinsic and extrinsic erythropoietin enhances neuroprotection against ischemia and reperfusion injury in vitro. J Neurochem 96(4):1101–1110. https://doi.org/10.1111/j.1471-4159.2005.03597.x
Luo B, Jiang M, Yang X, Zhang Z, Xiong J, Schluesener HJ, Zhang Z, Wu Y (2013) Erythropoietin is a hypoxia inducible factor-induced protective molecule in experimental autoimmune neuritis. Biochim Biophys Acta 1832(8):1260–1270. https://doi.org/10.1016/j.bbadis.2013.04.015
Ma S, Chen J, Chen C, Wei N, Xu J, Yang G, Wang N, Meng Y, Ren J, Xu Z (2018) Erythropoietin rescues memory impairment in a rat model of chronic cerebral hypoperfusion via the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β pathway. Mol Neurobiol 55(4):3290–3299. https://doi.org/10.1007/s12035-017-0568-5
Maggioni D, Nicolini G, Chiorazzi A, Meregalli C, Cavaletti G, Tredici G (2010) Different effects of erythropoietin in cisplatin- and docetaxel-induced neurotoxicity: an in vitro study. J Neurosci Res 88(14):3171–3179. https://doi.org/10.1002/jnr.22465
Maiese K, Chong ZZ, Shang YC (2008) OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. Trends Mol Med 14(5):219–227. https://doi.org/10.1016/j.molmed.2008.03.002
Manning BD, Toker A (2017) AKT/PKB Signaling: navigating the network. Cell 169(3):381–405. https://doi.org/10.1016/j.cell.2017.04.001
Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E (2014) PI3K/AKT signaling pathway and cancer: an updated review. Ann Med 46(6):372–383. https://doi.org/10.3109/07853890.2014.912836
Mofidi A, Bader A, Pavlica S (2011) The use of erythropoietin and its derivatives to treat spinal cord injury. Mini Rev Med Chem 11(9):763–770. https://doi.org/10.2174/138955711796355267
Nadiminty N, Lou W, Lee SO, Lin X, Trump DL, Gao AC (2006) Stat3 activation of NF-{kappa}B p100 processing involves CBP/p300-mediated acetylation. Proc Natl Acad Sci USA 103(19):7264–7269. https://doi.org/10.1073/pnas.0509808103 (Epub 2006 May 1)
O’Neill LA, Kaltschmidt C (1997) NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci 20(6):252–258. https://doi.org/10.1016/s0166-2236(96)01035-1
Park HA, Licznerski P, Alavian KN, Shanabrough M, Jonas EA (2015) Bcl-xL is necessary for neurite outgrowth in hippocampal neurons. Antioxid Redox Signal 22(2):93–108. https://doi.org/10.1089/ars.2013.5570
Quintavalle C, Incoronato M, Puca L, Acunzo M, Zanca C, Romano G, Garofalo M, Iaboni M, Croce CM, Condorelli G (2010) c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity. Cell Death Differ 17(12):1908–1916. https://doi.org/10.1038/cdd.2010.65
Raza M, Blair RE, Sombati S, Carter DS, Deshpande LS, DeLorenzo RJ (2004) Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy. Proc Natl Acad Sci USA 101:17522–17527. https://doi.org/10.1073/pnas.0408155101
Read DE, Gorman AM (2009) Involvement of Akt in neurite outgrowth. Cell Mol Life Sci 66(18):2975–2984. https://doi.org/10.1007/s00018-009-0057-8
Rivera-Cervantes MC, Jarero-Basulto JJ, Murguía-Castillo J, Marín-López AG, Gasca-Martínez Y, Cornelio-Martínez S, Beas-Zárate C (2019) The recombinant human erythropoietin administered in neonatal rats after excitotoxic damage induces molecular changes in the hippocampus. Front Neurosci 13:118
Rosenzweig MQ, Bender CM, Lucke JP, Yasko JM, Brufsky AM (2004) The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events. J Pain Symptom Manag 27(2):185–190. https://doi.org/10.1016/j.jpainsymman.2003.06.010
Sargin D, Friedrichs H, El-Kordi A, Ehrenreich H (2010) Erythropoietin as neuroprotective and neuroregenerative treatment strategy: comprehensive overview of 12 years of preclinical and clinical research. Best Pract Res Clin Anaesthesiol 24(4):573–594. https://doi.org/10.1016/j.bpa.2010.10.005
Schoemaker MH, Ros JE, Homan M, Trautwein C, Liston P, Poelstra K, van Goor H, Jansen PL, Moshage H (2002) Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes: NF-kappaB-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis. J Hepatol 36(6):742–750. https://doi.org/10.1016/s0168-8278(02)00063-6
Semenza GL (2007) Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE. https://doi.org/10.1126/stke.4072007cm8
Shang Y, Wu Y, Yao S, Wang X, Feng D, Yang W (2007) Protective effect of erythropoietin against ketamine-induced apoptosis in cultured rat cortical neurons: involvement of PI3K/Akt and GSK-3 beta pathway. Apoptosis 12(12):2187–2195. https://doi.org/10.1007/s10495-007-0141-1
Wenker SD, Chamorro ME, Vittori DC, Nesse AB (2013) Protective action of erythropoietin on neuronal damage induced by activated microglia. FEBS J 280(7):1630–1642
Simon F, Scheuerle A, Calzia E, Bassi G, Oter S, Duy CN, Kick J, Brückner UB, Radermacher P, Schelzig H (2008) Erythropoietin during porcine aortic balloon occlusion-induced ischemia/reperfusion injury. Crit Care Med 36(7):2143–2150
Simon F, Scheuerle A, Gröger M, Vcelar B, McCook O, Möller P, Georgieff M, Calzia E, Radermacher P, Schelzig H (2011) Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury. Intensive Care Med 37(9):1525–1533
Simon F, Erhart P, Vcelar B, Scheuerle A, Schelzig H, Oberhuber A (2016) Erythropoietin preconditioning improves clinical and histologic outcome in an acute spinal cord ischemia and reperfusion rabbit model. J Vasc Surg 64(6):1797–1804
Simon F, Floros N, Ibing W, Schelzig H, Knapsis A (2019) Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system. Neural Regen Res 14(8):1309–1312. https://doi.org/10.4103/1673-5374.253507
Simon F, Wagenhäuser MU, Busch A, Schelzig H, Gombert A (2020) Arteriogenesis of the spinal cord—the network challenge. Cells 9(2):501. https://doi.org/10.3390/cells9020501 (Published 2020 Feb 22)
Sirén AL, Knerlich F, Poser W, Gleiter CH, Brück W, Ehrenreich H (2001) Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol 101(3):271–276. https://doi.org/10.1007/s004010000297
Song JS, Cho KS, Yoon HK, Moon HS, Park SH (2005) Neutrophil elastase causes MUC5AC mucin synthesis via EGF receptor, ERK and NF-kB pathways in A549 cells. Korean J Intern Med 20(4):275–283. https://doi.org/10.3904/kjim.2005.20.4.275
Stark GR, Darnell JE Jr (2012) The JAK-STAT pathway at twenty. Immunity 36(4):503–514. https://doi.org/10.1016/j.immuni.2012.03.013
Sunters A, Fernández de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, Coffer PJ, Medema RH, Coombes RC, Lam W-FE (2003) FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 278(50):49795–49805. https://doi.org/10.1074/jbc.M309523200
Torup L (2007) Neuroprotection with or without erythropoiesis; sometimes less is more. Br J Pharmacol 8:1141–1142. https://doi.org/10.1038/sj.bjp.0707287 (Epub 2007 May 29)
Turkseven S, Kruger A, Mingone CJ, Kaminski P, Inaba M, Rodella LF, Ikehara S, Wolin MS, Abraham NG (2005) Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes. Am J Physiol Heart Circ Physiol 289(2):H701–H707. https://doi.org/10.1152/ajpheart.00024.2005
Ureña-Guerrero ME, Castañeda-Cabral JL, Rivera-Cervantes MC, Macias-Velez RJ, Jarero-Basulto JJ, Gudiño-Cabrera G, Beas-Zárate C (2020) Neuroprotective and neurorestorative effects of Epo and VEGF: perspectives for new therapeutic approaches to neurological diseases. Curr Pharm Des 26(12):1263–1276. https://doi.org/10.2174/1381612826666200114104342
Vittori DC, Chamorro ME, Hernández YV, Maltaneri RE, Nesse AB (2021) Erythropoietin and derivatives: potential beneficial effects on the brain. J Neurochem 158(5):1032–1057. https://doi.org/10.1111/jnc.15475 (Epub 2021 Aug 9)
Wang L, Zhang Z, Wang Y, Zhang R, Chopp M (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35(7):1732–1737. https://doi.org/10.1161/01.STR.0000132196.49028.a4 (Epub 2004 Jun 3)
Wang L, Chopp M, Gregg SR, Zhang RL, Teng H, Jiang A, Feng Y, Zhang ZG (2008) Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF. J Cereb Blood Flow Metab 28(7):1361–1368. https://doi.org/10.1038/jcbfm.2008.32
Watowich SS (2011) The erythropoietin receptor: molecular structure and hematopoietic signaling pathways. J Investig Med 59(7):1067–1072. https://doi.org/10.2310/JIM.0b013e31820fb28c
Wenker SD, Chamorro ME, Vittori DC, Nesse AB (2013) Protective action of erythropoietin on neuronal damage induced by activated microglia. FEBS J 280(7):1630–1642. https://doi.org/10.1111/febs.12172 (Epub 2013 Mar 1)
Won YJ, Yoo JY, Lee JH, Hwang SJ, Kim D, Hong HN (2007) Erythropoietin is neuroprotective on GABAergic neurons against kainic acid-excitotoxicity in the rat spinal cell cultures. Brain Res 1154:31–39. https://doi.org/10.1016/j.brainres.2007.04.010
Wu Y, Shang Y, Sun S, Liang H, Liu R (2007) Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3beta/caspase-3 mediated signaling pathway. Apoptosis 12(8):1365–1375. https://doi.org/10.1007/s10495-007-0065-9
Wu H, Wang H, Zhang W, Wei X, Zhao J, Yan P, Liu C (2015) rhEPO affects apoptosis in hippocampus of aging rats by upregulating SIRT1. Int J Clin Exp Pathol 8(6):6870–6880
Yamauchi T, Kaburagi Y, Ueki K, Tsuji Y, Stark GR, Kerr IM, Tsushima T, Akanuma Y, Komuro I, Tobe K, Yazaki Y, Kadowaki T (2013) Growth hormone and prolactin stimulate tyrosine phosphorylation of insulin receptor substrate-1, -2, and -3, their association with p85 phosphatidylinositol 3-kinase (PI3-kinase), and concomitantly PI3-kinase activation via JAK2 kinase. J Biol Chem 273:15719–15726
Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80(2):285–291. https://doi.org/10.1016/0092-8674(95)90411-5
Yoo J, Won Y, Lee J, Kim J, Sung I, Hwang S et al (2009) Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures. J Neurosci Res 87(1):150–163. https://doi.org/10.1002/jnr.21832
Zaheer A, Knight S, Zaheer A, Ahrens M, Sahu SK, Yang B (2008) Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3beta and caspase-3. Brain Res 1190:206–214. https://doi.org/10.1016/j.brainres.2007.11.011
Zhang F, Signore AP, Zhou Z, Wang S, Cao G, Chen J (2006) Erythropoietin protects CA1 neurons against global cerebral ischemia in rat: potential signaling mechanisms. J Neurosci Res 83(7):1241–1251. https://doi.org/10.1002/jnr.20816
Zhang F, Wang S, Cao G, Gao Y, Chen J (2007) Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia. Neurobiol Dis 25(1):45–53
Zhang LM, Zhang DX, Zhao XC, Sun W (2020) Retracted article: Erythropoietin rescues primary rat cortical neurons by altering the Nrf2:Bach1 ratio: roles of extracellular signal-regulated kinase 1/2. Neurochem Res 45(5):1244. https://doi.org/10.1007/s11064-017-2174-3
Zhao J, Li G, Zhang Y, Su X, Hang C (2011) The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant human erythropoietin (rhEPO) after experimental traumatic brain injury of rats. Cytokine 56(2):343–350. https://doi.org/10.1016/j.cyto.2011.07.018
Zheng J, Feng X, Hou L, Cui Y, Zhu L, Ma J, Xia Z, Zhou W, Chen H (2011) Latanoprost promotes neurite outgrowth in differentiated RGC-5 cells via the PI3K-Akt-mTOR signaling pathway. Cell Mol Neurobiol 31(4):597–604. https://doi.org/10.1007/s10571-011-9653-x
Zheng H, Wang X, Tang Z, Zheng W, Li Z (2013) The PI3K/Akt and ERK1/2 signaling pathways mediate the erythropoietin-modulated calcium influx in kainic acid-induced epilepsy. NeuroReport 24(6):335–341. https://doi.org/10.1097/WNR.0b013e32835ffe03
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Cornelio-Martinez S: writing—original draft preparation, investigation, term; Castañeda-Arellano R: conceptualization, writing, project supervision, final manuscript approval, funding acquisition, project administration.
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Sergio, CM., Rolando, CA. Erythropoietin regulates signaling pathways associated with neuroprotective events. Exp Brain Res 240, 1303–1315 (2022). https://doi.org/10.1007/s00221-022-06331-9
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DOI: https://doi.org/10.1007/s00221-022-06331-9