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2000
Volume 24, Issue 9
  • ISSN: 1871-5273
  • E-ISSN: 1996-3181

Abstract

Background

Epilepsy is a widespread neurological disorder, particularly affecting children and the elderly, presenting complex and varied challenges in management. Recently, erythropoietin has gained significant attention due to its neuroprotective effects, which have been demonstrated experimentally in various neurological conditions, including epilepsy. This review aims to analyze current literature on the role of erythropoietin in seizures and epilepsy.

Method

A comprehensive literature search was conducted through PubMed, Scopus, and Web of Science databases up to September 30, 2024. The search terms included “Epilepsy AND Erythropoietin”, “Seizures AND Erythropoietin,” and “Status Epilepticus AND Erythropoietin”, applied to titles, abstracts, and keywords.

Results

The review highlights ongoing debates surrounding erythropoietin's effects on epilepsy. While erythropoietin shows potential in mitigating seizure-induced brain damage and modulating cellular processes such as anti-apoptotic and anti-inflammatory pathways, its clinical application is complicated by conflicting evidence. Some studies suggest that erythropoietin may trigger seizures, with factors such as dosage and individual patient characteristics potentially influencing this risk.

Conclusion

Experimental studies suggest that erythropoietin offers neuroprotective benefits in epilepsy. However, its possible pro-convulsant effects-which might be linked to erythropoietin-induced hypertension, rapid increases in hematocrit levels, dosage, or individual patient characteristics-raise safety concerns. These risks complicate its clinical use, making it premature to endorse erythropoietin as a treatment fully. Future research should focus on non-erythropoietic derivatives that retain neuroprotective effects without stimulating red blood cell production, thereby reducing risks, such as hypertension and thrombosis. Well-designed clinical trials and further investigation into erythropoietin’s mechanisms are essential to clarify its role and optimize its therapeutic potential in epilepsy.

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References

  1. WHO. Epilepsy, Fact Sheet, World Health Organization.2023Available from: https://www.who.int/news-room/fact-sheets/detail/epilepsy Accessed on 26 Novamber 2023.
  2. EnglandM.J. LivermanC.T. SchultzA.M. StrawbridgeL.M. Epilepsy across the spectrum: Promoting health and understanding.Epilepsy Behav.201225226627610.1016/j.yebeh.2012.06.01623041175
     [Google Scholar]
  3. FisherR.S. BoasW.E. BlumeW. Epileptic seizures and epilepsy: Definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE).Epilepsia200546447047210.1111/j.0013‑9580.2005.66104.x15816939
     [Google Scholar]
  4. DevinskyO. VezzaniA. O’BrienT.J. Epilepsy.Nat. Rev. Dis. Primers2018411802410.1038/nrdp.2018.2429722352
     [Google Scholar]
  5. WirrellE. TinuperP. PeruccaE. MoshéS.L. Introduction to the epilepsy syndrome papers.Epilepsia20226361330133210.1111/epi.1726235503711
     [Google Scholar]
  6. Falco-Walter J. Epilepsy—definition, classification, pathophysiology, and epidemiology.Semin. Neurol.202040661762310.1055/s‑0040‑171871933155183
     [Google Scholar]
  7. WylieT.S.D. MurrN.I. Status Epilepticus.In: StatPearls.Treasure Island, FLStatPearls Publishing2023
     [Google Scholar]
  8. KwanP. ArzimanoglouA. BergA.T. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.Epilepsia20105161069107710.1111/j.1528‑1167.2009.02397.x19889013
     [Google Scholar]
  9. BeghiE. GiussaniG. CostaC. The epidemiology of epilepsy in older adults: A narrative review by the ILAE Task Force on Epilepsy in the Elderly.Epilepsia202364358660110.1111/epi.1749436625133
     [Google Scholar]
  10. ShintonR.A. GillJ.S. MelnickS.C. GuptaA.K. BeeversD.G. The frequency, characteristics and prognosis of epileptic seizures at the onset of stroke.J. Neurol. Neurosurg. Psychiatry198851227327610.1136/jnnp.51.2.2733346694
     [Google Scholar]
  11. HesdorfferD.C. HauserW.A. AnnegersJ.F. KokmenE. RoccaW.A. Dementia and adult-onset unprovoked seizures.Neurology199646372773010.1212/WNL.46.3.7278618673
     [Google Scholar]
  12. RohracherA. ReiterD.P. BrigoF. Status epilepticus in the elderly—A retrospective study on 120 patients.Epilepsy Res.201612731732310.1016/j.eplepsyres.2016.08.01627694014
     [Google Scholar]
  13. EnglotD.J. ChangE.F. VechtC.J. Epilepsy and brain tumors.Handb. Clin. Neurol.201613426728510.1016/B978‑0‑12‑802997‑8.00016‑526948360
     [Google Scholar]
  14. NashefL. SoE.L. RyvlinP. TomsonT. Unifying the definitions of sudden unexpected death in epilepsy.Epilepsia201253222723310.1111/j.1528‑1167.2011.03358.x22191982
     [Google Scholar]
  15. MudigoudarB. WhelessJ.W. Sudden Unexpected Death in Epilepsy (SUDEP): How do we prevent this childhood tragedy?J. Pediatr. Pharmacol. Ther.20222729910110.5863/1551‑6776‑27.2.9935241979
     [Google Scholar]
  16. MartinR.C. GriffithH.R. FaughtE. GilliamF. MackeyM. VogtleL. Cognitive functioning in community dwelling older adults with chronic partial epilepsy.Epilepsia200546229830310.1111/j.0013‑9580.2005.02104.x15679511
     [Google Scholar]
  17. GriffithH.R. MartinR.C. BambaraJ.K. MarsonD.C. FaughtE. Older adults with epilepsy demonstrate cognitive impairments compared with patients with amnestic mild cognitive impairment.Epilepsy Behav.20068116116810.1016/j.yebeh.2005.09.00416266829
     [Google Scholar]
  18. NovakA. VizjakK. RakusaM. Cognitive impairment in people with epilepsy.J. Clin. Med.202211126710.3390/jcm1101026735012007
     [Google Scholar]
  19. GibbsJ.W.III ShumateM.D. CoulterD.A. Differential epilepsy-associated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons.J. Neurophysiol.19977741924193810.1152/jn.1997.77.4.19249114245
     [Google Scholar]
  20. PalmaE. RosetiC. MaiolinoF. GABAA-current rundown of temporal lobe epilepsy is associated with repetitive activation of GABAA “phasic” receptors.Proc. Natl. Acad. Sci. USA200710452209442094810.1073/pnas.071052210518083839
     [Google Scholar]
  21. KhazipovR. GABAergic synchronization in epilepsy.Cold Spring Harb. Perspect. Med.201662a02276410.1101/cshperspect.a02276426747834
     [Google Scholar]
  22. CurtisD.R. FelixD. McLellanH. GABA and hippocampal inhibition.Br. J. Pharmacol.197040488188310.1111/j.1476‑5381.1970.tb10663.x5495182
     [Google Scholar]
  23. ConnorsB.W. Initiation of synchronized neuronal bursting in neocortex.Nature1984310597968568710.1038/310685a06147755
     [Google Scholar]
  24. MilesR. WongR.K. Inhibitory control of local excitatory circuits in the guinea‐pig hippocampus.J. Physiol.1987388161162910.1113/jphysiol.1987.sp0166343656200
     [Google Scholar]
  25. DuringM.J. SpencerD.D. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain.Lancet199334188611607161010.1016/0140‑6736(93)90754‑58099987
     [Google Scholar]
  26. WilsonC.L. MaidmentN.T. ShomerM.H. Comparison of seizure related amino acid release in human epileptic hippocampus versus a chronic, kainate rat model of hippocampal epilepsy.Epilepsy Res.199626124525410.1016/S0920‑1211(96)00057‑58985704
     [Google Scholar]
  27. Ronne-EngströmE. HilleredL. FlinkR. SpännareB.O. UngerstedtU. CarlsonH. Intracerebral microdialysis of extracellular amino acids in the human epileptic focus.J. Cereb. Blood Flow Metab.199212587387610.1038/jcbfm.1992.1191506452
     [Google Scholar]
  28. ChapmanA.G. Glutamate receptors in epilepsy.Prog Brain Res199811637138310.1016/S0079‑6123(08)60449‑59932389
     [Google Scholar]
  29. Barker-HaliskiM. WhiteH.S. Glutamatergic mechanisms associated with seizures and epilepsy.Cold Spring Harb. Perspect. Med.201558a02286310.1101/cshperspect.a02286326101204
     [Google Scholar]
  30. ChapmanA.G. Glutamate and epilepsy.J. Nutr.20001304Suppl.1043S1045S10.1093/jn/130.4.1043S10736378
     [Google Scholar]
  31. ZhengZ. ZhangL. QuY. Mesenchymal stem cells protect against hypoxia-ischemia brain damage by enhancing autophagy through brain derived neurotrophic factor/mammalin target of rapamycin signaling pathway.Stem Cells20183671109112110.1002/stem.280829451335
     [Google Scholar]
  32. AliS.O. ShahinN.N. SafarM.M. RizkS.M. Therapeutic potential of endothelial progenitor cells in a rat model of epilepsy: Role of autophagy.J. Adv. Res.20191810111210.1016/j.jare.2019.01.01330847250
     [Google Scholar]
  33. DavenportC.J. Jann BrownW. BabbT.L. Sprouting of GABAergic and mossy fiber axons in dentate gyrus following intrahippocampal kainate in the rat.Exp. Neurol.1990109218019010.1016/0014‑4886(90)90072‑Z1696207
     [Google Scholar]
  34. ChoC.H. Frontier of Epilepsy Research - mTOR signaling pathway.Exp. Mol. Med.201143523127410.3858/emm.2011.43.5.03221467839
     [Google Scholar]
  35. AydinA. Genc̨K. AkhisarogluM. YorukogluK. GokmenN. GonulluE. Erythropoietin exerts neuroprotective effect in neonatal rat model of hypoxic-ischemic brain injury.Brain Dev.200325749449810.1016/S0387‑7604(03)00039‑113129593
     [Google Scholar]
  36. ChenS. XuD. FanL. FangZ. WangX. LiM. Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy.Front. Mol. Neurosci.20221479725310.3389/fnmol.2021.79725335069111
     [Google Scholar]
  37. HardinghamG.E. BadingH. Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders.Nat. Rev. Neurosci.2010111068269610.1038/nrn291120842175
     [Google Scholar]
  38. KimJ.K. ChoJ. KimS.H. Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy.J. Clin. Invest.2019129104207422310.1172/JCI12703231483294
     [Google Scholar]
  39. CrinoP.B. The mTOR signalling cascade: Paving new roads to cure neurological disease.Nat. Rev. Neurol.201612737939210.1038/nrneurol.2016.8127340022
     [Google Scholar]
  40. LiW. WuJ. ZengY. ZhengW. Neuroinflammation in epileptogenesis: From pathophysiology to therapeutic strategies.Front. Immunol.202314126924110.3389/fimmu.2023.126924138187384
     [Google Scholar]
  41. Aguilar-CastilloM.J. Cabezudo-GarcíaP. Ciano-PetersenN.L. Immune mechanism of epileptogenesis and related therapeutic strategies.Biomedicines202210371610.3390/biomedicines1003071635327518
     [Google Scholar]
  42. SokolovaT.V. ZabrodskayaY.M. LitovchenkoA.V. Relationship between neuroglial apoptosis and neuroinflammation in the epileptic focus of the brain and in the blood of patients with drug-resistant epilepsy.Int. J. Mol. Sci.202223201256110.3390/ijms23201256136293411
     [Google Scholar]
  43. HenshallD.C. SimonR.P. Epilepsy and apoptosis pathways.J. Cereb. Blood Flow Metab.200525121557157210.1038/sj.jcbfm.960014915889042
     [Google Scholar]
  44. HenshallD.C. SkradskiS.L. LanJ.Q. RenT. SimonR.P. Increased Bcl-w expression following focally evoked limbic seizures in the rat.Neurosci. Lett.2001305315315610.1016/S0304‑3940(01)01849‑311403928
     [Google Scholar]
  45. BengzonJ. MohapelP. EkdahlC.T. LindvallO. Neuronal apoptosis after brief and prolonged seizures.Prog Brain Res200213511111910.1016/S0079‑6123(02)35011‑812143333
     [Google Scholar]
  46. ChangS.J. YuB.C. Mitochondrial matters of the brain: Mitochondrial dysfunction and oxidative status in epilepsy.J. Bioenerg. Biomembr.201042645745910.1007/s10863‑010‑9317‑421086030
     [Google Scholar]
  47. LinT.K. ChenS.D. LinK.J. ChuangY.C. Seizure-induced oxidative stress in status epilepticus: Is antioxidant beneficial?Antioxidants (Basel)2020911102910.3390/antiox911102933105652
     [Google Scholar]
  48. AguiarC.C.T. AlmeidaA.B. AraújoP.V.P. Oxidative stress and epilepsy: Literature review.Oxid. Med. Cell. Longev.2012201211210.1155/2012/79525922848783
     [Google Scholar]
  49. YilgorA. DemirC. Determination of oxidative stress level and some antioxidant activities in refractory epilepsy patients.Sci. Rep.2024141668810.1038/s41598‑024‑57224‑638509121
     [Google Scholar]
  50. Ben-MenachemE. KyllermanM. MarklundS. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies.Epilepsy Res.2000401333910.1016/S0920‑1211(00)00096‑610771256
     [Google Scholar]
  51. SharmaS. PuttacharyS. ThippeswamyT. Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy.J. Neurosci. Res.201997111363137710.1002/jnr.2420529230865
     [Google Scholar]
  52. PotschkaH. BrodieM.J. Pharmacoresistance.Handb. Clin. Neurol.201210874175710.1016/B978‑0‑444‑52899‑5.00025‑322939063
     [Google Scholar]
  53. VolkH.A. LöscherW. Multidrug resistance in epilepsy: Rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures.Brain200512861358136810.1093/brain/awh43715716304
     [Google Scholar]
  54. BrandtC. BethmannK. GastensA.M. LöscherW. The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy.Neurobiol. Dis.200624120221110.1016/j.nbd.2006.06.01416928449
     [Google Scholar]
  55. KwanP. BrodieM.J. Potential role of drug transporters in the pathogenesis of medically intractable epilepsy.Epilepsia200546222423510.1111/j.0013‑9580.2005.31904.x15679503
     [Google Scholar]
  56. BergA.T. Identification of pharmacoresistant epilepsy.Neurol. Clin.20092741003101310.1016/j.ncl.2009.06.00119853220
     [Google Scholar]
  57. LöscherW. PotschkaH. SisodiyaS.M. VezzaniA. Drug resistance in epilepsy: Clinical impact, potential mechanisms, and new innovative treatment options.Pharmacol. Rev.202072360663810.1124/pr.120.01953932540959
     [Google Scholar]
  58. MulaM. KannerA.M. JettéN. SanderJ.W. Psychiatric comorbidities in people with epilepsy.Neurol. Clin. Pract.2021112e112e12010.1212/CPJ.000000000000087433842079
     [Google Scholar]
  59. LiY. ZhangS. SnyderM.P. MeadorK.J. Precision medicine in women with epilepsy: The challenge, systematic review, and future direction.Epilepsy Behav.202111810792810.1016/j.yebeh.2021.10792833774354
     [Google Scholar]
  60. LezaicN. RoussyJ. MassonH. JettéN. KeezerM.R. Epilepsy in the elderly: Unique challenges in an increasingly prevalent population.Epilepsy Behav.202010210672410.1016/j.yebeh.2019.10672431816480
     [Google Scholar]
  61. KerrM.P. MensahS. BesagF. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy.Epilepsia201152112133213810.1111/j.1528‑1167.2011.03276.x21955156
     [Google Scholar]
  62. ReissmannK.R. Studies on the mechanism of erythropoietic stimulation in parabiotic rats during hypoxia.Blood19505437238010.1182/blood.V5.4.372.37215411424
     [Google Scholar]
  63. FisherJ.W. Erythropoietin: Physiology and pharmacology update.Exp. Biol. Med. (Maywood)2003228111410.1177/15353702032280010112524467
     [Google Scholar]
  64. ReyF. BalsariA. GiallongoT. Erythropoietin as a neuroprotective molecule: An overview of its therapeutic potential in neurodegenerative diseases.ASN Neuro20191110.1177/175909141987142031450955
     [Google Scholar]
  65. MerelliA. CzornyjL. LazarowskiA. Erythropoietin: A neuroprotective agent in cerebral hypoxia, neurodegeneration, and epilepsy.Curr. Pharm. Des.201319386791680110.2174/138161281131938001123530506
     [Google Scholar]
  66. KumralA. TugyanK. GonencS. Protective effects of erythropoietin against ethanol-induced apoptotic neurodegenaration and oxidative stress in the developing C57BL/6 mouse brain.Brain Res. Dev. Brain Res.2005160214615610.1016/j.devbrainres.2005.08.00616236368
     [Google Scholar]
  67. SunJ. MartinJ.M. VanderpoelV. SumbriaR.K. The promises and challenges of erythropoietin for treatment of Alzheimer’s disease.Neuromolecular Med.2019211122410.1007/s12017‑019‑08524‑y30656553
     [Google Scholar]
  68. ErbaşO. ÇınarB.P. SolmazV. ÇavuşoğluT. AteşU. The neuroprotective effect of erythropoietin on experimental Parkinson model in rats.Neuropeptides2015491510.1016/j.npep.2014.10.00325464888
     [Google Scholar]
  69. EidT. BrinesM. Recombinant human erythropoietin for neuroprotection: What is the evidence?Clin. Breast Cancer20023Suppl. 3S109S11510.3816/CBC.2002.s.02112533271
     [Google Scholar]
  70. GencS. KorogluT.F. GencK. Erythropoietin and the nervous system.Brain Res.200410001-2193110.1016/j.brainres.2003.12.03715053948
     [Google Scholar]
  71. MerelliA. CzornyjL. LazarowskiA. Erythropoietin as a new therapeutic opportunity in brain inflammation and neurodegenerative diseases.Int. J. Neurosci.20151251179379710.3109/00207454.2014.98932125405533
     [Google Scholar]
  72. NoguchiC.T. AsavaritikraiP. TengR. JiaY. Role of erythropoietin in the brain.Crit. Rev. Oncol. Hematol.200764215917110.1016/j.critrevonc.2007.03.00117482474
     [Google Scholar]
  73. HemaniS. LaneO. AgarwalS. YuS.P. WoodburyA. Systematic Review of Erythropoietin (EPO) for neuroprotection in human studies.Neurochem. Res.202146473273910.1007/s11064‑021‑03242‑z33521906
     [Google Scholar]
  74. XiongY. LuD. QuC. Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice.J. Neurosurg.2008109351052110.3171/JNS/2008/109/9/051018759585
     [Google Scholar]
  75. XiongY. MahmoodA. MengY. Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose.J. Neurosurg.2010113359860810.3171/2009.9.JNS0984419817538
     [Google Scholar]
  76. WangY. ZhangZ.G. RhodesK. Post‐ischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia.Br. J. Pharmacol.200715181377138410.1038/sj.bjp.070728517603558
     [Google Scholar]
  77. Elliot-PortalE. LaouafaS. Arias-ReyesC. JanesT.A. JosephV. SolizJ. Brain-derived erythropoietin protects from intermittent hypoxia-induced cardiorespiratory dysfunction and oxidative stress in mice.Sleep2018417zsy07210.1093/sleep/zsy07229697839
     [Google Scholar]
  78. ImJ.H. YeoI.J. HwangC.J. LeeK.S. HongJ.T. PEGylated erythropoietin protects against brain injury in the MCAO-induced stroke model by blocking NF-κB activation.Biomol. Ther. (Seoul)202028215216210.4062/biomolther.2019.14731813204
     [Google Scholar]
  79. MorishitaE. MasudaS. NagaoM. YasudaY. SasakiR. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death.Neuroscience199676110511610.1016/S0306‑4522(96)00306‑58971763
     [Google Scholar]
  80. WeiS. LuoC. YuS. Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway.Exp. Cell Res.2017361234235210.1016/j.yexcr.2017.11.00229102603
     [Google Scholar]
  81. AssandriR. EggerM. GassmannM. Erythropoietin modulates intracellular calcium in a human neuroblastoma cell line.J. Physiol.1999516Pt 234335210.1111/j.1469‑7793.1999.0343v.x10087335
     [Google Scholar]
  82. ChenZ.Y. AsavaritikraiP. PrchalJ.T. NoguchiC.T. Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation.J. Biol. Chem.200728235258752588310.1074/jbc.M70198820017604282
     [Google Scholar]
  83. BlixtJ. GunnarsonE. WanecekM. Erythropoietin attenuates the brain edema response after experimental traumatic brain injury.J. Neurotrauma201835467168010.1089/neu.2017.501529179621
     [Google Scholar]
  84. BrinesM.L. GhezziP. KeenanS. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury.Proc. Natl. Acad. Sci. USA20009719105261053110.1073/pnas.97.19.1052610984541
     [Google Scholar]
  85. SchoenerB.B.J. Erythropoietin Stimulating Agents.In: StatPearls.Treasure Island, FLStatPearls Publishing2024(Updated 2024 Jul 14).
     [Google Scholar]
  86. ChenJ. YangZ. ZhangX. Carbamylated erythropoietin: A prospective drug candidate for neuroprotection.Biochem. Insights20168Suppl. 1252926862298
     [Google Scholar]
  87. MesgarpourB. HeidingerB.H. RothD. SchmitzS. WalshC.D. HerknerH. Harms of off-label erythropoiesis-stimulating agents for critically ill people.Cochrane Libr.201720191CD01096910.1002/14651858.CD010969.pub228841235
     [Google Scholar]
  88. LittonE. LathamP. InmanJ. LuoJ. AllanP. Safety and efficacy of erythropoiesis-stimulating agents in critically ill patients admitted to the intensive care unit: A systematic review and meta-analysis.Intensive Care Med.20194591190119910.1007/s00134‑019‑05686‑y31297547
     [Google Scholar]
  89. BruceG. SchulgaP. ReynoldsB.C. Use of erythropoiesis-stimulating agents in children with chronic kidney disease: A systematic review.Clin. Kidney J.20221581483150510.1093/ckj/sfac05835892014
     [Google Scholar]
  90. QinN. QinH. Efficacy and safety of high and low dose recombinant human erythropoietin on neurodevelopment of premature infants.Medicine (Baltimore)202110018e2580510.1097/MD.000000000002580533950982
     [Google Scholar]
  91. Sanchez-GonzalezL.R. Castro-MelendezS.E. Angeles-TorresA.C. Castro-CortinaN. Escobar-ValenciaA. Quiroga-GarzaA. Efficacy and safety of adjuvant recombinant human erythropoietin and ferrous sulfate as treatment for iron deficiency anemia during the third trimester of pregnancy.Eur. J. Obstet. Gynecol. Reprod. Biol.2016205323610.1016/j.ejogrb.2016.08.00427566219
     [Google Scholar]
  92. MikatiM.A. HokayemJ.A.E. SabbanM.E.E. Effects of a single dose of erythropoietin on subsequent seizure susceptibility in rats exposed to acute hypoxia at P10.Epilepsia200748117518110.1111/j.1528‑1167.2006.00900.x17241225
     [Google Scholar]
  93. NadamJ. NavarroF. SanchezP. Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus.Neurobiol. Dis.200725241242610.1016/j.nbd.2006.10.00917166730
     [Google Scholar]
  94. ÜzümG. Sarper DilerA. BahçekapılıN. Ziya ZiylanY. Erythropoietin prevents the increase in blood–brain barrier permeability during pentylentetrazol induced seizures.Life Sci.200678222571257610.1016/j.lfs.2005.10.02716343549
     [Google Scholar]
  95. RosetiC. CifelliP. RuffoloG. Erythropoietin increases GABAA currents in human cortex from TLE patients.Neuroscience202043915316210.1016/j.neuroscience.2019.04.01331047977
     [Google Scholar]
  96. KawakamiM. SekiguchiM. SatoK. KozakiS. TakahashiM. Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia.J. Biol. Chem.200127642394693947510.1074/jbc.M10583220011504731
     [Google Scholar]
  97. EidT. BrinesM.L. CeramiA. Increased expression of erythropoietin receptor on blood vessels in the human epileptogenic hippocampus with sclerosis.J. Neuropathol. Exp. Neurol.2004631738310.1093/jnen/63.1.7314748563
     [Google Scholar]
  98. OttC. MartensH. HassounaI. Widespread expression of erythropoietin receptor in brain and its induction by injury.Mol. Med.201521180381510.2119/molmed.2015.0019226349059
     [Google Scholar]
  99. NobiliP. NikolićL. ShenW. PristovJ.B. Can glial cells save neurons in epilepsy?Neural Regen. Res.20231871417142210.4103/1673‑5374.36028136571336
     [Google Scholar]
  100. JubinskyP.T. KrijanovskiO.I. NathanD.G. TavernierJ. SieffC.A. The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor.Blood19979051867187310.1182/blood.V90.5.18679292519
     [Google Scholar]
  101. BrinesM. CeramiA. Emerging biological roles for erythropoietin in the nervous system.Nat. Rev. Neurosci.20056648449410.1038/nrn168715928718
     [Google Scholar]
  102. AlnaeeliM. WangL. PiknovaB. RogersH. LiX. NoguchiC.T. Erythropoietin in brain development and beyond.Anat. Res. Int.2012201211510.1155/2012/95326422567318
     [Google Scholar]
  103. SanchezP.E. NavarroF.P. FaresR.P. Erythropoietin receptor expression is concordant with erythropoietin but not with common β chain expression in the rat brain throughout the life span.J. Comp. Neurol.2009514440341410.1002/cne.2202019330822
     [Google Scholar]
  104. OstrowskiD. HeinrichR. Alternative erythropoietin receptors in the nervous system.J. Clin. Med.2018722410.3390/jcm702002429393890
     [Google Scholar]
  105. SeegerN. ZellingerC. RodeA. The erythropoietin-derived peptide mimetic pHBSP affects cellular and cognitive consequences in a rat post-status epilepticus model.Epilepsia201152122333234310.1111/j.1528‑1167.2011.03302.x22050420
     [Google Scholar]
  106. HaraT. NakamuraK. MatsuiM. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.Nature2006441709588588910.1038/nature0472416625204
     [Google Scholar]
  107. CaoL. XuJ. LinY. ZhaoX. LiuX. ChiZ. Autophagy is upregulated in rats with status epilepticus and partly inhibited by Vitamin E.Biochem. Biophys. Res. Commun.2009379494995310.1016/j.bbrc.2008.12.17819138675
     [Google Scholar]
  108. BuckmasterP.S. IngramE.A. WenX. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy.J. Neurosci.200929258259826910.1523/JNEUROSCI.4179‑08.200919553465
     [Google Scholar]
  109. HuangX. ZhangH. YangJ. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy.Neurobiol. Dis.201040119319910.1016/j.nbd.2010.05.02420566381
     [Google Scholar]
  110. ZengL.H. RensingN.R. WongM. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy.J. Neurosci.200929216964697210.1523/JNEUROSCI.0066‑09.200919474323
     [Google Scholar]
  111. LiQ. HanY. DuJ. Recombinant human erythropoietin protects against hippocampal damage in developing rats with seizures by modulating autophagy via the S6 protein in a time-dependent manner.Neurochem. Res.201843246547610.1007/s11064‑017‑2443‑129238892
     [Google Scholar]
  112. LiQ. HanY. DuJ. Recombinant human erythropoietin protects against brain injury through blunting the mTORC1 pathway in the developing brains of rats with seizures.Life Sci.2018194152510.1016/j.lfs.2017.12.01429233655
     [Google Scholar]
  113. LaplanteM. SabatiniD.M. mTOR signaling in growth control and disease.Cell2012149227429310.1016/j.cell.2012.03.01722500797
     [Google Scholar]
  114. BahçekapılıN. Akgün-DarK. AlbenizI. Erythropoietin pretreatment suppresses seizures and prevents the increase in inflammatory mediators during pentylenetetrazole-induced generalized seizures.Int. J. Neurosci.20141241076277010.3109/00207454.2013.87893524397543
     [Google Scholar]
  115. CaiM. LinW. The function of NF-Kappa B during epilepsy, a potential therapeutic target.Front. Neurosci.20221685139410.3389/fnins.2022.85139435360161
     [Google Scholar]
  116. SözmenŞ.Ç. KurulS.H. YişU. TuğyanK. BaykaraB. YılmazO. Neuroprotective effects of recombinant human erythropoietin in the developing brain of rat after lithium-pilocarpine induced status epilepticus.Brain Dev.201234318919510.1016/j.braindev.2011.05.00221600713
     [Google Scholar]
  117. HuangY.G. WangJ.C. WenX.N. Erythropoietin preconditioning on hippocampus neuronal apoptosis following status epilepticus induced by Li-pilocarpine in rats through anti-caspase-3 expression.Neurol. India2006541586310.4103/0028‑3886.2470816679645
     [Google Scholar]
  118. JunY JiangTaoX YuanGui H Erythropoietin pre-treatment prevents cognitive impairments following status epilepticus in rats.Brain Res.20091282576610.1016/j.brainres.2009.05.06219497315
     [Google Scholar]
  119. YangJ. HuangY. YuX. SunH. LiY. DengA. Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats.Acta Neurobiol. Exp. (Warsz.)200767214114810.55782/ane‑2007‑164117691221
     [Google Scholar]
  120. YuJ. ShiZ. SuX. Expression of Bcl-2 and Bad in hippocampus of status epileptic rats and molecular mechanism of intervened recombinant human erythropoietin.Exp. Ther. Med.201816284785510.3892/etm.2018.625030116338
     [Google Scholar]
  121. XiaoxiaoPan XiaoqianGong Lili Pan LiyuLu. Erythropoietin relieves neuronal apoptosis in epilepsy rats via TGF-β/Smad signaling pathway.Cell. Mol. Biol.2023691023924310.14715/cmb/2023.69.10.3537953557
     [Google Scholar]
  122. ZhengH. WangX. TangZ. ZhengW. LiZ. The PI3K/Akt and ERK1/2 signaling pathways mediate the erythropoietin-modulated calcium influx in kainic acid-induced epilepsy.Neuroreport201324633534110.1097/WNR.0b013e32835ffe0323518641
     [Google Scholar]
  123. Sánchez-AlegríaK. Flores-LeónM. Avila-MuñozE. Rodríguez-CoronaN. AriasC. PI3K signaling in neurons: A central node for the control of multiple functions.Int. J. Mol. Sci.20181912372510.3390/ijms1912372530477115
     [Google Scholar]
  124. NitulescuG. Van De VenterM. NitulescuG. The Akt pathway in oncology therapy and beyond (Review).Int. J. Oncol.20185362319233110.3892/ijo.2018.459730334567
     [Google Scholar]
  125. KapucuA. ÜzümG. KaptanZ. Akgün-DarK. Effects of erythropoietin pretreatment on single dose pentylentetrazole-induced seizures in rats.Biotech. Histochem.202095641842710.1080/10520295.2020.171339832003592
     [Google Scholar]
  126. KondoA. ShingoT. YasuharaT. Erythropoietin exerts anti-epileptic effects with the suppression of aberrant new cell formation in the dentate gyrus and upregulation of neuropeptide Y in seizure model of rats.Brain Res.2009129612713610.1016/j.brainres.2009.08.02519695235
     [Google Scholar]
  127. ChuK. JungK.H. LeeS.T. Erythropoietin reduces epileptogenic processes following status epilepticus.Epilepsia200849101723173210.1111/j.1528‑1167.2008.01644.x18479396
     [Google Scholar]
  128. JungK.H. ChuK. LeeS.T. Molecular alterations underlying epileptogenesis after prolonged febrile seizure and modulation by erythropoietin.Epilepsia201152354155010.1111/j.1528‑1167.2010.02916.x21269282
     [Google Scholar]
  129. LazarowskiA. CzornyjL. LubieniekiF. GirardiE. VazquezS. D’GianoC. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy.Epilepsia200748Suppl. 514014910.1111/j.1528‑1167.2007.01302.x17910594
     [Google Scholar]
  130. MerelliA. RamosA.J. LazarowskiA. AuzmendiJ. Convulsive stress mimics brain hypoxia and promotes the P-Glycoprotein (P-gp) and erythropoietin receptor overexpression.Front. Neurosci.20191375010.3389/fnins.2019.0075031379495
     [Google Scholar]
  131. BarotN. NeiM. Autonomic aspects of sudden unexpected death in epilepsy (SUDEP).Clin. Auton. Res.201929215116010.1007/s10286‑018‑0576‑130456432
     [Google Scholar]
  132. NeiM. Cardiac effects of seizures.Epilepsy Curr.200994919510.1111/j.1535‑7511.2009.01303.x19693322
     [Google Scholar]
  133. AuzmendiJ. BuchholzB. SalgueroJ. Pilocarpine-induced status epilepticus is associated with P-glycoprotein induction in cardiomyocytes, electrocardiographic changes, and sudden death.Pharmaceuticals (Basel)20181112110.3390/ph1101002129462915
     [Google Scholar]
  134. AuzmendiJ. PuchuluM.B. RodríguezJ.C.G. BalaszczukA.M. LazarowskiA. MerelliA. EPO and EPO-receptor system as potential actionable mechanism for the protection of brain and heart in refractory epilepsy and SUDEP.Curr. Pharm. Des.202026121356136410.2174/138161282666620021909554832072891
     [Google Scholar]
  135. KapucuA. KaptanZ. DarK.A. KalelerI. Effects of erythropoietin pretreatment on liver, kidney, heart tissue in pentylentetrazol-induced seizures; evaluation in terms of oxidative markers, prolidase and sialic acid/pentilentetrazol-induklu nobetlerde eritropoietin on tedavisinin karaciger, bobrek, kalp dokusu uzerine etkileri; oksidatif markirlar, prolidaz ve sialik asit acisindan degerlendirme.J Istanbul Fac Med2021844464471Available from: link.gale.com/apps/doc/A685929068/HRCA?u=anon~bf5af658sid=sitemapxid=fa9a348d
    [Google Scholar]
  136. BulurŞ. DemirŞ. BahadirA. AnkaraliS. ÖzmerdivenliR. BeyazçiçekE. The effects of erythropoietin on the penicillin induced epileptiform activity in rats.Kafkas Univ. Vet. Fak. Derg.2016222215220
     [Google Scholar]
  137. MengY. XiongY. MahmoodA. ZhangY. QuC. ChoppM. Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats.J. Neurosurg.2011115355056010.3171/2011.3.JNS10172121495821
     [Google Scholar]
  138. ZhaoH.W. LuY. LiX.Y. Intranasal administration of low dosage recombinant human erythropoietin inhibits seizure in rats.Zhejiang Da Xue Xue Bao Yi Xue Ban200938656557110.3785/j.issn.1008‑9292.2009.06.00320014480
     [Google Scholar]
  139. LagartoA. BuenoV. GuerraI. Absence of hematological side effects in acute and subacute nasal dosing of erythropoietin with a low content of sialic acid.Exp. Toxicol. Pathol.201163656356710.1016/j.etp.2010.04.00820488687
     [Google Scholar]
  140. ParraA.L. RodriguezJ.C. Nasal neuro EPO could be a reliable choice for neuroprotective stroke treatment.Cent. Nerv. Syst. Agents Med. Chem.2012121606810.2174/18715241280022914322376076
     [Google Scholar]
  141. García-RodríguezJ.C. Sosa TesteI. The nasal route as a potential pathway for delivery of erythropoietin in the treatment of acute ischemic stroke in humans.ScientificWorldJournal2009997098110.1100/tsw.2009.10319768354
     [Google Scholar]
  142. MerelliA CaltanaL LazarowskiA BruscoA Experimental evidence of the potential use of erythropoietin by intranasal administration as a neuroprotective agent in cerebral hypoxia.dmdi201126265910.1515/dmdi.2011.00721756166
     [Google Scholar]
  143. CaoG.Y. YuD.D. YuY.S. Effect of erythropoietin carried by stearic acid-grafted chitosan micelle on epilepsy seizure in mice.Chinese Journal of Pharmaceutical Biotechnology20132015356
     [Google Scholar]
  144. ZellingerC. SeegerN. HadamitzkyM. Impact of the erythropoietin-derived peptide mimetic Epotris on the histopathological consequences of status epilepticus.Epilepsy Res.201196324124910.1016/j.eplepsyres.2011.06.00921741213
     [Google Scholar]
  145. VittoriD.C. ChamorroM.E. HernándezY.V. MaltaneriR.E. NesseA.B. Erythropoietin and derivatives: Potential beneficial effects on the brain.J. Neurochem.202115851032105710.1111/jnc.1547534278579
     [Google Scholar]
  146. MahmoudA.T. El DeghadyA.A. Erythropoietin in the serum and cerebrospinal fluid of epileptic children.J Alex J Pediatr200519185192
     [Google Scholar]
  147. ShiL.M. ChenR.J. ZhangH. JiangC.M. GongJ. Cerebrospinal fluid neuron specific enolase, interleukin-1β and erythropoietin concentrations in children after seizures.Childs Nerv. Syst.201733580581110.1007/s00381‑017‑3359‑428236069
     [Google Scholar]
  148. BeccariM. Seizures in dialysis patients treated with recombinant erythropoietin. Review of the literature and guidelines for prevention.Int. J. Artif. Organs199417151310.1177/0391398894017001028188400
     [Google Scholar]
  149. TatlıB. BozganD. EkiciB. GürbüzerC.A. Erythropoietin-induced cluster of seizures in two children with cerebral palsy.Acta Neurol. Belg.2020120496997010.1007/s13760‑019‑01207‑231555981
     [Google Scholar]
  150. GlassH.C. WusthoffC.J. ComstockB.A. Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.Pediatr. Res.202394125225910.1038/s41390‑022‑02398‑w36470964
     [Google Scholar]
  151. EdmundsM.E. WallsJ. TuckerB. Seizures in haemodialysis patients treated with recombinant human erythropoietin.Nephrol. Dial. Transplant.1989412106510692517327
     [Google Scholar]
  152. BeccariM. RomagnoniM. SorgatoG. Seizures in dialysis patients treated with recombinant erythropoietin.Nephrol. Dial. Transplant.19951034234247792048
     [Google Scholar]
  153. CengizK. IşlekI. Does erythropoietin cause epilepsy.Nephron199673232032110.1159/0001890638773367
     [Google Scholar]
  154. BeccariM. Erythropoietin-induced epilepsy in hemodialysis patients?Nephron J.199878335410.1159/0000449569546707
     [Google Scholar]
  155. ChoK.H. MinK. LeeS.H. LeeS. AnS.A. KimM. Clinical trial of erythropoietin in young children with cerebral palsy.J. Child Neurol.201631101227123410.1177/088307381665003827233796
     [Google Scholar]
  156. Erythropoetin Neuroprotection for Neonatal Cardiac SurgeryNCT00513240.2007Available from: https://clinicaltrials.gov/study/NCT00513240
    [Google Scholar]
  157. High-dose Erythropoietin for Asphyxia and EncephalopathyNCT02811263.2016Available from: https://clinicaltrials.gov/study/NCT02811263
    [Google Scholar]
  158. WassinkG. DavidsonJ.O. CrisostomoA. Recombinant erythropoietin does not augment hypothermic white matter protection after global cerebral ischaemia in near-term fetal sheep.Brain Commun.202133fcab17210.1093/braincomms/fcab17234409290
     [Google Scholar]
  159. LiY. ZhangJ. WangH. Does erythropoietin affect the outcome and complication rates of patient with traumatic brain injury? A pooled-analysis.Neurol. Sci.20224363783379310.1007/s10072‑022‑05877‑435044560
     [Google Scholar]
  160. ZhengQ. XuJ. LuoX. Letter to the Editor: Does erythropoietin affect the outcome and complication rates of patient with traumatic brain injury? A pooled analysis.Neurol Sci202344135535610.1007/s10072‑022‑06359‑336030463
     [Google Scholar]
  161. MohebpourV. RahimiM. ShadniaS. MostafazadehB. Talab EviniP.E. The adverse reactions of erythropoietin in methanol toxicity: A descriptive study.Int J Med Toxicol Forensic Med20241414307810.32598/ijmtfm.v14i1.43078
     [Google Scholar]
  162. DelantyN. VaughanC. FruchtS. StubgenP. Erythropoietin-associated hypertensive posterior leukoencephalopathy.Neurology199749368668910.1212/WNL.49.3.6869305323
     [Google Scholar]
  163. PotterT. SchaeferT.J. Hypertensive encephalopathy.In: StatPearls.Treasure Island, FLStatPearls Publishing2024Updated 2024 Feb 2.
     [Google Scholar]
  164. ErbayraktarS. GrassoG. SfacteriaA. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo.Proc. Natl. Acad. Sci. USA2003100116741674610.1073/pnas.103175310012746497
     [Google Scholar]
  165. LeistM. GhezziP. GrassoG. Derivatives of erythropoietin that are tissue protective but not erythropoietic.Science2004305568123924210.1126/science.109831315247477
     [Google Scholar]
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Erythropoietin for Seizures and Epilepsy: Neuroprotective Effects, Mechanisms, and Contradictory Risks
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 24, 701 (2025); https://doi.org/10.2174/0118715273367111250307081826
/content/journals/cnsnddt/10.2174/0118715273367111250307081826
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  • Article Type:     Review Article
Keyword(s): Epilepsy; erythropoietin; neuroprotection; recombinant human erythropoietin; seizures; status epilepticus

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