{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:20:37Z","timestamp":1788880837625,"version":"build-2803163510"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2018,3,1]],"date-time":"2018-03-01T00:00:00Z","timestamp":1519862400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"funder":[{"name":"College of Arts and Sciences at Kent State University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2018,10]]},"DOI":"10.1007\/s12035-018-0971-6","type":"journal-article","created":{"date-parts":[[2018,3,1]],"date-time":"2018-03-01T16:30:24Z","timestamp":1519921824000},"page":"8051-8058","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Erythropoietin Upregulates Brain Hemoglobin Expression and Supports Neuronal Mitochondrial Activity"],"prefix":"10.1007","volume":"55","author":[{"given":"N. K.","family":"Singhal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Alkhayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Shelestak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Clements","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Freeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"McDonough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,3,1]]},"reference":[{"key":"971_CR1","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1002\/1531-8249(200012)48:6<893::AID-ANA10>3.0.CO;2-B","volume":"48","author":"C Bjartmar","year":"2000","unstructured":"Bjartmar C, Kidd G, M\u00f6rk S, Rudick R, Trapp BD (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetylaspartate in chronic multiple sclerosis patients. Ann Neurol 48:893\u2013901","journal-title":"Ann Neurol"},{"key":"971_CR2","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1001\/archneur.58.1.65","volume":"58","author":"N Stefano De","year":"2001","unstructured":"De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65\u201370","journal-title":"Arch Neurol"},{"key":"971_CR3","doi-asserted-by":"publisher","first-page":"6777","DOI":"10.1073\/pnas.87.17.6777","volume":"87","author":"JD England","year":"1990","unstructured":"England JD, Gamboni F, Levinson SR, Finger TE (1990) Changed distribution of sodium channels along demyelinated axons. Proc Natl Acad Sci U S A 87:6777\u20136780","journal-title":"Proc Natl Acad Sci U S A"},{"key":"971_CR4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.jns.2005.03.031","volume":"233","author":"PK Stys","year":"2005","unstructured":"Stys PK (2005) General mechanisms of axonal damage and its prevention. J Neurol Sci 233:3\u201313","journal-title":"J Neurol Sci"},{"key":"971_CR5","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1038\/nrn2023","volume":"7","author":"SG Waxman","year":"2006","unstructured":"Waxman SG (2006) Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 7:932\u2013941","journal-title":"Nat Rev Neurosci"},{"key":"971_CR6","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1093\/brain\/awl007","volume":"129","author":"C Confavreux","year":"2006","unstructured":"Confavreux C, Vukusic S (2006) Natural history of multiple sclerosis: a unifying concept. Brain 129:606\u2013616","journal-title":"Brain"},{"key":"971_CR7","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1002\/ana.20736","volume":"59","author":"R Dutta","year":"2006","unstructured":"Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB et al (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478\u2013489","journal-title":"Ann Neurol"},{"key":"971_CR8","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.jns.2009.01.009","volume":"279","author":"A Pandit","year":"2009","unstructured":"Pandit A, Vadnal J, Houston S, Freeman E, McDonough J (2009) Impaired regulation of electron transport chain subunit genes by nuclear respiratory factor 2 in multiple sclerosis. J Neurol Sci 279:14\u201320","journal-title":"J Neurol Sci"},{"key":"971_CR9","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1002\/ana.22109","volume":"69","author":"GR Campbell","year":"2011","unstructured":"Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM et al (2011) Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 69:481\u2013492","journal-title":"Ann Neurol"},{"key":"971_CR10","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.bbadis.2011.01.012","volume":"1812","author":"L Broadwater","year":"2011","unstructured":"Broadwater L, Pandit A, Azzam S, Clements R, Vadnal J, Sulak M, Yong VW, Freeman EJ et al (2011) Analysis of the mitochondrial proteome in multiple sclerosis cortex. Biochim Biophys Acta 1812:630\u2013641","journal-title":"Biochim Biophys Acta"},{"key":"971_CR11","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s00401-012-1052-y","volume":"125","author":"ME Witte","year":"2013","unstructured":"Witte ME, Nijland PG, Drexhage JA, Gerritsen W, Geerts D, van Het Hof B, Reijerkerk A, de Vries HE et al (2013) Reduced expression of PGC-1partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex. Acta Neuropathol 125:231\u2013243","journal-title":"Acta Neuropathol"},{"key":"971_CR12","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1212\/WNL.62.4.624","volume":"62","author":"Y Ge","year":"2004","unstructured":"Ge Y, Gonen O, Inglese M, Babb JS, Markowitz CE, Grossman RI (2004) Neuronal cell injury precedes brain atrophy in multiple sclerosis. Neurology 62:624\u2013627","journal-title":"Neurology"},{"key":"971_CR13","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.neuroimage.2007.02.036","volume":"36","author":"S Cader","year":"2007","unstructured":"Cader S, Johansen-Berg H, Wylezinska M, Palace J, Behrens TE, Smith S, Matthews PM (2007) Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis. NeuroImage 36:19\u201327","journal-title":"NeuroImage"},{"key":"971_CR14","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.neuint.2015.08.015","volume":"90","author":"Y Xuan","year":"2015","unstructured":"Xuan Y, Yan G, Wu R, Huang Q, Li X, Xu H (2015) The cuprizone-induced changes in (1)H-MRS metabolites and oxidative parameters in C57BL\/6 mouse brain: Effects of quetiapine. Neurochem Int 90:185\u2013192","journal-title":"Neurochem Int"},{"key":"971_CR15","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.neubiorev.2014.10.004","volume":"47","author":"J Praet","year":"2014","unstructured":"Praet J, Guglielmetti C, Berneman Z, Van der Linden A, Ponsaerts P (2014) Cellular and molecular neuropathology of the cuprizone mouse model: Clinical relevance for multiple sclerosis. Neurosci Biobehav Rev 47:485\u2013505","journal-title":"Neurosci Biobehav Rev"},{"key":"971_CR16","doi-asserted-by":"publisher","first-page":"628","DOI":"10.2119\/molmed.2011.00457","volume":"18","author":"N Hagemeyer","year":"2012","unstructured":"Hagemeyer N, Boretius S, Ott C, Von Streitberg A, Welpinghus H, Sperling S et al (2012) Erythropoietin attenuates neurological and histological consequences of toxic demyelination in mice. Mol Med 18:628\u2013635","journal-title":"Mol Med"},{"key":"971_CR17","doi-asserted-by":"crossref","first-page":"19488","DOI":"10.1016\/S0021-9258(17)32195-6","volume":"269","author":"S Masuda","year":"1994","unstructured":"Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R (1994) A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269:19488\u201319493","journal-title":"J Biol Chem"},{"key":"971_CR18","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s00429-005-0019-3","volume":"210","author":"W Knabe","year":"2005","unstructured":"Knabe W, Sir\u00e9n AL, Ehrenreich H, Kuhn HJ (2005) Expression patterns of erythropoietin and its receptor in the developing spinal cord and dorsal root ganglia. Anat Embryol (Berl) 210:209\u2013219","journal-title":"Anat Embryol (Berl)"},{"key":"971_CR19","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1007\/s00429-003-0365-y","volume":"207","author":"W Knabe","year":"2004","unstructured":"Knabe W, Knerlich F, Washausen S, Kietzmann T, Sir\u00e9n AL, Brunnett G et al (2004) Expression patterns of erythropoietin and its receptor in the developing midbrain. Anat Embryol (Berl) 207:503\u2013512","journal-title":"Anat Embryol (Berl)"},{"key":"971_CR20","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1203\/00006450-199801000-00007","volume":"43","author":"SE Juul","year":"1998","unstructured":"Juul SE, Anderson DK, Li Y, Christensen RD (1998) Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr Res 43:40\u201349","journal-title":"Pediatr Res"},{"key":"971_CR21","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1038\/mp.2015.212","volume":"21","author":"I Hassouna","year":"2016","unstructured":"Hassouna I, Ott C, W\u00fcstefeld L, Offen N, Neher RA, Mitkovski M, Winkler D, Sperling S et al (2016) Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus. Mol Psychiatry 21:1752\u20131767","journal-title":"Mol Psychiatry"},{"key":"971_CR22","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/j.bpa.2010.10.005","volume":"24","author":"D Sargin","year":"2010","unstructured":"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 24:573\u2013594","journal-title":"Best Pract Res Clin Anaesthesiol"},{"key":"971_CR23","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.nurt.2008.10.041","volume":"6","author":"AL Siren","year":"2009","unstructured":"Siren AL, Fasshauer T, Bartels C, Ehrenreich H (2009) Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics 6:108\u2013127","journal-title":"Neurotherapeutics"},{"key":"971_CR24","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1159\/000068926","volume":"83","author":"A Kumral","year":"2003","unstructured":"Kumral A, Ozer E, Yilmaz O, Akhisaroglu M, Gokmen N, Duman N, Ulukus C, Genc S et al (2003) Neuroprotective effect of erythropoietin on hypoxic-ischemic brain injury in neonatal rats. Biol Neonate 83:224\u2013228","journal-title":"Biol Neonate"},{"key":"971_CR25","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/S0006-2952(99)00277-4","volume":"59","author":"A Chattopadhyay","year":"2000","unstructured":"Chattopadhyay A, Choudhury TD, Bandyopadhyay D, Datta AG (2000) Protective effect of erythropoietin on the oxidative damage of erythrocyte membrane by hydroxyl radical. Biochem Pharmacol 59:419\u2013425","journal-title":"Biochem Pharmacol"},{"key":"971_CR26","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1097\/00004647-199906000-00007","volume":"19","author":"M Bernaudin","year":"1999","unstructured":"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 19:643\u2013651","journal-title":"J Cereb Blood Flow Metab"},{"key":"971_CR27","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/jcbfm.2008.152","volume":"29","author":"DW Schelshorn","year":"2009","unstructured":"Schelshorn DW, Schneider A, Kuschinsky W, Weber D, Kr\u00fcger C, Dittgen T, B\u00fcrgers HF, Sabouri F et al (2009) Expression of hemoglobin in rodent neurons. J Cereb Blood Flow Metab 29:585\u2013595","journal-title":"J Cereb Blood Flow Metab"},{"key":"971_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12031-015-0711-6","volume":"59","author":"N Brown","year":"2016","unstructured":"Brown N, Alkhayer K, Clements R, Singhal N, Gregory R, Azzam S, Li S, Freeman E et al (2016) Neuronal hemoglobin expression and its relevance to multiple sclerosis neuropathology. J Mol Neurosci 59:1\u201317","journal-title":"J Mol Neurosci"},{"key":"971_CR29","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1083\/jcb.38.1.158","volume":"38","author":"C Schnaitman","year":"1968","unstructured":"Schnaitman C, Greenawalt JW (1968) Enzymatic properties of the inner and outer membranes of rat liver mitochondria. J Cell Biol 38:158\u2013175","journal-title":"J Cell Biol"},{"key":"971_CR30","doi-asserted-by":"publisher","first-page":"2385","DOI":"10.1007\/s11064-013-1151-8","volume":"38","author":"S Li","year":"2013","unstructured":"Li S, Clements R, Sulak M, Gregory R, Freeman E, McDonough J (2013) Decreased NAA in gray matter is correlated with decreased availability of acetate in white matter in postmortem multiple sclerosis cortex. Neurochem Res 38:2385\u20132396","journal-title":"Neurochem Res"},{"key":"971_CR31","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.brainres.2008.06.129","volume":"1229","author":"L Schmued","year":"2008","unstructured":"Schmued L, Bowyer J, Cozart M, Heard D, Binienda Z, Paule M (2008) Introducing Black-Gold II, a highly soluble gold phosphate complex with several unique advantages for the histochemical localization of myelin. Brain Res 1229:210\u2013217","journal-title":"Brain Res"},{"key":"971_CR32","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/978-1-62703-308-4_10","volume":"982","author":"I Cervellini","year":"2013","unstructured":"Cervellini I, Ghezzi P, Mengozzi M (2013) Therapeutic efficacy of erythropoietin in experimental autoimmune encephalomyelitis in mice, a model of multiple sclerosis. Methods Mol Biol 982:163\u2013173","journal-title":"Methods Mol Biol"},{"key":"971_CR33","doi-asserted-by":"publisher","first-page":"15170","DOI":"10.1523\/JNEUROSCI.4349-14.2015","volume":"35","author":"NK Singhal","year":"2015","unstructured":"Singhal NK, Li S, Arning E, Alkhayer K, Clements R, Sarcyk Z, Dassanayake RS, Brasch NE et al (2015) Changes in methionine metabolism and histone H3 trimethylation are linked to mitochondrial defects in multiple sclerosis. J Neurosci 35:15170\u201315186","journal-title":"J Neurosci"},{"issue":"Suppl 2","key":"971_CR34","doi-asserted-by":"publisher","first-page":"S181","DOI":"10.1038\/sj.cdd.4401504","volume":"11","author":"MB S\u00e4ttler","year":"2004","unstructured":"S\u00e4ttler MB, Merkler D, Maier K, Stadelmann C, Ehrenreich H, B\u00e4hr M et al (2004) Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis. Cell Death Differ 11(Suppl 2):S181\u2013S192","journal-title":"Cell Death Differ"},{"key":"971_CR35","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1038\/35088074","volume":"412","author":"M Digicaylioglu","year":"2001","unstructured":"Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412:641\u2013647","journal-title":"Nature"},{"key":"971_CR36","doi-asserted-by":"publisher","first-page":"4741","DOI":"10.1111\/bph.13248","volume":"172","author":"LY Horng","year":"2015","unstructured":"Horng LY, Hsu PL, Chen LW, Tseng WZ, Hsu KT, Wu CL, Wu RT (2015) Activating mitochondrial function and haemoglobin expression with EH-201, an inducer of erythropoietin in neuronal cells, reverses memory impairment. Br J Pharmacol 172:4741\u20134756","journal-title":"Br J Pharmacol"},{"key":"971_CR37","doi-asserted-by":"publisher","first-page":"15454","DOI":"10.1073\/pnas.0813216106","volume":"106","author":"M Biagioli","year":"2009","unstructured":"Biagioli M, Pinto M, Cesselli D, Zaninello M, Lazarevic D, Roncaglia P et al (2009) Unexpected expression of \u03b1- and \u03b2-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci U S A 106:15454\u201315459","journal-title":"Proc Natl Acad Sci U S A"},{"key":"971_CR38","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1159\/000017321","volume":"20","author":"JB Clark","year":"1998","unstructured":"Clark JB (1998) N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20:271\u2013276","journal-title":"Dev Neurosci"},{"key":"971_CR39","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1089\/08977150152693683","volume":"18","author":"S Signoretti","year":"2001","unstructured":"Signoretti S, Marmarou A, Tavazzi B, Lazzarino G, Beaumont A, Vagnozzi R (2001) N-Acetylaspartate reduction as a measure of injury severity and mitochondrial dysfunction following diffuse traumatic brain injury. J Neurotrauma 18:977\u2013991","journal-title":"J Neurotrauma"},{"key":"971_CR40","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1002\/cne.22062","volume":"515","author":"F Richter","year":"2009","unstructured":"Richter F, Meurers BH, Zhu C, Medvedeva VP, Chesselet MF (2009) Neurons express hemoglobin alpha- and beta-chains in rat and human brains. J Comp Neurol 515:538\u2013547","journal-title":"J Comp Neurol"},{"key":"971_CR41","doi-asserted-by":"publisher","first-page":"537","DOI":"10.3233\/JAD-2010-101485","volume":"23","author":"I Ferrer","year":"2011","unstructured":"Ferrer I, G\u00f3mez A, Carmona M, Huesa G, Porta S, Riera-Codina M et al (2011) Neuronal hemoglobin is reduced in Alzheimer\u2019s disease, argyrophilic grain disease, Parkinson\u2019s disease, and dementia with Lewy bodies. J Alzheimers Dis 23:537\u2013550","journal-title":"J Alzheimers Dis"},{"key":"971_CR42","doi-asserted-by":"publisher","first-page":"16021","DOI":"10.1038\/npjparkd.2016.21","volume":"2","author":"J Freed","year":"2016","unstructured":"Freed J, Chakrabarti L (2016) Defining a role for hemoglobin in Parkinson\u2019s disease. NPJ Parkinsons Dis 2:16021","journal-title":"NPJ Parkinsons Dis"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s12035-018-0971-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-018-0971-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-018-0971-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T02:51:13Z","timestamp":1660531873000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s12035-018-0971-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,1]]},"references-count":42,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["971"],"URL":"https:\/\/doi.org\/10.1007\/s12035-018-0971-6","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,1]]},"assertion":[{"value":"15 August 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}