{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T03:55:58Z","timestamp":1772078158710,"version":"3.50.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Neurotrophic factors (NTF) play key roles in the survival of neurons, making them promising candidates for therapy of neurodegenerative diseases. In the case of the inner ear, sensorineural hearing loss (SNHL) is characterized over time by a degeneration of the primary auditory neurons, the spiral ganglion neurons (SGN). It is well known that selected NTF can protect SGN from degeneration, which positively influences the outcome of cochlear implants, the treatment of choice for patients with profound to severe SNHL. However, the outcome of studies investigating protective effects of NTF on auditory neurons are in some cases of high variability. We hypothesize that the factor origin may be one aspect that affects the neuroprotective potential. The aim of this study was to investigate the neuroprotective potential of <jats:italic>human<\/jats:italic> and <jats:italic>mouse<\/jats:italic> Erythropoietin (EPO) and Cometin on rat SGN. SGN were isolated from neonatal rats (P 2\u20135) and cultured in serum-free medium. EPO and Cometin of mouse and human origin were added in concentrations of 0.1, 1, and 10\u2009ng\/mL and 0.1, 1, and 10\u2009\u03bcg\/mL, respectively. The SGN survival rate and morphology, and the neurite outgrowth were determined and compared to negative (no additives) and positive (brain-derived neurotrophic factor, BDNF) controls. A neuroprotective effect of 10\u2009\u03bcg\/mL human Cometin comparable to that obtained with BDNF was observed in the SGN-culture. In contrast, mouse Cometin was ineffective. A similar influence of 10\u2009\u03bcg\/mL human and mouse and 1\u2009\u03bcg\/mL human Cometin on the length of regenerated neurites compared to BDNF was also detected. No other Cometin-conditions, and none of the EPO-conditions tested had neuroprotective or neuritogenic effects or influenced the neuronal morphology of the SGN. The neuroprotective effect of 10\u2009\u03bcg\/mL human Cometin on SGN indicates it is a potentially interesting protein for the supportive treatment of inner ear disorders. The finding that mouse Cometin had no effect on the SGN in the parallel-performed experiments underlines the importance of species origin of molecules being screened for therapeutic purpose.<\/jats:p>","DOI":"10.3389\/fnins.2023.1224463","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T06:43:55Z","timestamp":1691736235000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["\u201cOf mice and men\u201d: the relevance of Cometin and Erythropoietin origin for its effects on murine spiral ganglion neuron survival and neurite outgrowth in vitro"],"prefix":"10.3389","volume":"17","author":[{"given":"Jana","family":"Schwieger","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziwen","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Lenarz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon","family":"Munro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth A.","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Scheper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.neulet.2005.11.013","article-title":"Recombinant human erythropoietin prevents ischemia-induced apoptosis and necrosis in explant cultures of the rat organ of Corti","volume":"396","author":"Andreeva","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.toxlet.2018.04.007","article-title":"Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice","volume":"291","author":"B\u00e4chinger","year":"2018","journal-title":"Toxicol. Lett."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1016\/j.neuro.2005.01.016","article-title":"Erythropoietin: a novel neuroprotective cytokine","volume":"26","author":"Bartesaghi","year":"2005","journal-title":"Neurotoxicology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.heares.2008.07.003","article-title":"Neurite outgrowth on cultured spiral ganglion neurons induced by erythropoietin","volume":"243","author":"Berkingali","year":"2008","journal-title":"Hear. Res."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2983","DOI":"10.1007\/s00221-019-05644-6","article-title":"Pleiotrophin increases neurite length and number of spiral ganglion neurons in vitro","volume":"237","author":"Bertram","year":"2019","journal-title":"Exp. Brain Res."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"12724","DOI":"10.1074\/jbc.M116.725325","article-title":"A single amino acid difference between mouse and human 5-lipoxygenase activating protein (FLAP) explains the speciation and differential pharmacology of novel FLAP inhibitors","volume":"291","author":"Blevitt","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"220","DOI":"10.3390\/audiolres11020020","article-title":"Meta-analysis\u2014correlation between spiral ganglion cell counts and speech perception with a Cochlear implant","volume":"11","author":"Cheng","year":"2021","journal-title":"Audiol. Res."},{"key":"ref7","doi-asserted-by":"crossref","DOI":"10.1016\/bs.apcsb.2018.01.007","volume-title":"Peptide derivatives of erythropoietin in the treatment of Neuroinflammation and neurodegeneration","author":"Ercan","year":"2018"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1097\/00001756-200102120-00019","article-title":"LIF is more potent than BDNF in promoting neurite outgrowth of mammalian auditory neurons in vitro","volume":"12","author":"Gillespie","year":"2001","journal-title":"Neuroreport"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1002\/ar.22587","article-title":"The Trk a, B, C\u2019s of neurotrophins in the cochlea","volume":"295","author":"Green","year":"2012","journal-title":"Anat Rec (Hoboken)"},{"key":"ref10","first-page":"213","article-title":"Effect of erythropoietin on acoustically traumatized rat cochlea: an immunohistochemical study","volume":"36","author":"G\u00fcrgen","year":"2014","journal-title":"Anal. Quant. Cytopathol. Histpathol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.heares.2010.10.003","article-title":"Spiral ganglion cell survival after round window membrane application of brain-derived neurotrophic factor using gelfoam as carrier","volume":"272","author":"Havenith","year":"2011","journal-title":"Hear. Res."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1159\/000445174","article-title":"Erythropoietin","volume":"47","author":"Jelkmann","year":"2016","journal-title":"Front. Horm. Res."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.expneurol.2011.09.027","article-title":"Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo","volume":"233","author":"J\u00f8rgensen","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.neuropharm.2013.08.008","article-title":"TGF-beta superfamily member activin a acts with BDNF and erythropoietin to improve survival of spiral ganglion neurons in vitro","volume":"75","author":"Kaiser","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1002\/cne.22582","article-title":"Brain-derived neurotrophic factor promotes cochlear spiral ganglion cell survival and function in deafened, developing cats","volume":"519","author":"Leake","year":"2011","journal-title":"J. Comp. Neurol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"S123","DOI":"10.1055\/s-0043-101812","article-title":"Cochlear implant \u2013 state of the art","volume":"96","author":"Lenarz","year":"2017","journal-title":"Laryngorhinootologie"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1515\/dmdi.2009.24.2-4.229","article-title":"Molecular modelling of CYP2F substrates: comparison of naphthalene metabolism by human, rat and mouse CYP2F subfamily enzymes","volume":"24","author":"Lewis","year":"2009","journal-title":"Drug Metabol. Drug Interact."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1097\/01.mlg.0000199400.08550.3f","article-title":"The effect of erythropoietin on gentamicin-induced auditory hair cell loss","volume":"116","author":"Monge","year":"2006","journal-title":"Laryngoscope"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1177\/000348941112001108","article-title":"Protective effect of systemic administration of erythropoietin on auditory brain stem response and compound action potential thresholds in an animal model of cochlear implantation","volume":"120","author":"Quesnel","year":"2011","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref21","article-title":"Recombinant human Meteorin-like\/METRNL protein","year":""},{"key":"ref1001","article-title":"Recombinant mouse Meteorin-like\/METRNL protein","year":""},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1126\/science.abn3027","article-title":"Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase","volume":"376","author":"Reboll","year":"2022","journal-title":"Science"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1097\/01.moo.0000180919.68812.b9","article-title":"Strategies to preserve or regenerate spiral ganglion neurons","volume":"13","author":"Roehm","year":"2005","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1534\/genetics.104.027177","article-title":"Identification of a novel point mutation of mouse proto-oncogene c-kit through N-ethyl-N-nitrosourea MutagenesisSequence data from this article have been deposited with the EMBL\/GenBank data libraries under accession nos. AY536430 and AY536431","volume":"169","author":"Ruan","year":"2005","journal-title":"Genetics"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1146\/annurev.neuro.25.112701.142849","article-title":"Auditory system development: primary auditory neurons and their targets","volume":"25","author":"Rubel","year":"2002","journal-title":"Annu. Rev. Neurosci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1097\/MAO.0000000000002624","article-title":"Steroid nomenclature in inner ear therapy","volume":"41","author":"Salt","year":"2020","journal-title":"Otol. Neurotol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1002\/jnr.21964","article-title":"Effects of delayed treatment with combined GDNF and continuous electrical stimulation on spiral ganglioncell survival in deafened guinea pigs","volume":"87","author":"Scheper","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"559","DOI":"10.3390\/brainsci10080559","article-title":"Consecutive treatment with brain-derived neurotrophic factor and electrical stimulation has a protective effect on primary auditory neurons","volume":"10","author":"Scheper","year":"2020","journal-title":"Brain Sci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.jneumeth.2016.05.001","article-title":"Establishment of a long-term spiral ganglion neuron culture with reduced glial cell number: effects of AraC on cell composition and neurons","volume":"268","author":"Schwieger","year":"2016","journal-title":"J. Neurosci. Methods"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"91131","DOI":"10.1177\/2041731420911313","article-title":"Alginate-encapsulated brain-derived neurotrophic factor\u2013overexpressing mesenchymal stem cells are a promising drug delivery system for protection of auditory neurons","volume":"11","author":"Schwieger","year":"2020","journal-title":"J. Tissue Eng."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0133680","article-title":"Neuronal survival, morphology and outgrowth of spiral ganglion neurons using a defined growth factor combination","volume":"10","author":"Schwieger","year":"2015","journal-title":"PLoS One"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1038\/nri2017","article-title":"Humanized mice in translational biomedical research","volume":"7","author":"Shultz","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2020\/8831735","article-title":"Atrial natriuretic peptide improves neurite outgrowth from spiral ganglion neurons in vitro through a cGMP-dependent manner","volume":"2020","author":"Sun","year":"2020","journal-title":"Neural Plast."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e0224022","DOI":"10.1371\/journal.pone.0224022","article-title":"BDNF, NT-3 and Trk receptor agonist monoclonal antibodies promote neuron survival, neurite extension, and synapse restoration in rat cochlea ex vivo models relevant for hidden hearing loss","volume":"14","author":"Szobota","year":"2019","journal-title":"PLoS One"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"7119","DOI":"10.1021\/acs.jmedchem.5b00516","article-title":"Functional profiling of 2-Aminopyrimidine histamine H4 receptor modulators","volume":"58","author":"Tichenor","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.heares.2007.03.003","article-title":"Time course of cochlear electrophysiology and morphology after combined administration of kanamycin and furosemide","volume":"231","author":"Versnel","year":"2007","journal-title":"Hear. Res."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"787","DOI":"10.3390\/brainsci10110787","article-title":"BDNF outperforms TrkB agonist 7,8,3\u2019-THF in preserving the auditory nerve in deafened Guinea pigs","volume":"10","author":"Vink","year":"2020","journal-title":"Brain Sci."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1111\/jnc.15475","article-title":"Erythropoietin and derivatives: potential beneficial effects on the brain","volume":"158","author":"Vittori","year":"2021","journal-title":"J. Neurochem."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/s41392-022-00998-w","article-title":"Recombinant human erythropoietin ameliorates cognitive dysfunction of APP\/PS1 mice by attenuating neuron apoptosis via HSP90\u03b2","volume":"7","author":"Wan","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1097\/00001756-200512190-00008","article-title":"Brain-derived neurotrophic factor\/glial cell line-derived neurotrophic factor survival effects on auditory neurons are not limited by dexamethasone","volume":"16","author":"Wefstaedt","year":"2005","journal-title":"Neuroreport"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.heares.2016.07.019","article-title":"Drug discovery for hearing loss: phenotypic screening of chemical compounds on primary cultures of the spiral ganglion","volume":"349","author":"Whitlon","year":"2017","journal-title":"Hear. Res."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.neuroscience.2007.01.036","article-title":"Culture conditions determine the prevalence of bipolar and monopolar neurons in cultures of dissociated spiral ganglion","volume":"146","author":"Whitlon","year":"2007","journal-title":"Neuroscience"},{"key":"ref43","article-title":"World Health Organization","year":"2021"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1124\/jpet.108.138776","article-title":"MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a selective microsomal prostaglandin E synthase-1 inhibitor, relieves pyresis and pain in preclinical models of inflammation","volume":"326","author":"Xu","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/aps.2016.9","article-title":"Metrnl: a secreted protein with new emerging functions","volume":"37","author":"Zheng","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"2669","DOI":"10.3892\/ijmm.2018.3455","article-title":"Protective effect of adenovirus-mediated erythropoietin expression on the spiral ganglion neurons in the rat inner ear","volume":"41","author":"Zhong","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1523\/JNEUROSCI.4678-11.2012","article-title":"Inner hair cells are not required for survival of spiral ganglion neurons in the adult cochlea","volume":"32","author":"Zilberstein","year":"2012","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1224463\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T06:44:06Z","timestamp":1691736246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1224463\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,10]]},"references-count":48,"alternative-id":["10.3389\/fnins.2023.1224463"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2023.1224463","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,10]]},"article-number":"1224463"}}