{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:43:21Z","timestamp":1787168601968,"version":"build-2736575974"},"reference-count":53,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T00:00:00Z","timestamp":1631318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1182584"],"award-info":[{"award-number":["OPP1182584"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Perinatal hypoxic-ischemic (HI) brain injury, often in conjunction with an inflammatory insult, is the most common cause of death or disability in neonates. Therapeutic hypothermia (TH) is the standard of care for HI encephalopathy in term and near-term infants. However, TH may not always be available or efficacious, creating a need for novel or adjunctive neurotherapeutics. Using a near-term model of inflammation-sensitized HI brain injury in postnatal day (P) 17 ferrets, animals were randomized to either the control group (n = 43) or the HI-exposed groups: saline vehicle (Veh; n = 42), Ur (uridine monophosphate, n = 23), Epo (erythropoietin, n = 26), or TH (n = 24) to test their respective therapeutic effects. Motor development was assessed from P21 to P42 followed by analysis of cortical anatomy, ex vivo MRI, and neuropathology. HI animals took longer to complete the motor assessments compared to controls, which was exacerbated in the Ur group. Injury resulted in thinned white matter tracts and narrowed cortical sulci and gyri, which was mitigated in Epo-treated animals in addition to normalization of cortical neuropathology scores to control levels. TH and Epo treatment also resulted in region-specific improvements in diffusion parameters on ex vivo MRI; however, TH was not robustly neuroprotective in any behavioral or neuropathological outcome measures. Overall, Ur and TH did not provide meaningful neuroprotection after inflammation-sensitized HI brain injury in the ferret, and Ur appeared to worsen outcomes. By comparison, Epo appears to provide significant, though not complete, neuroprotection in this model.<\/jats:p>","DOI":"10.3390\/ijms22189841","type":"journal-article","created":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T21:45:57Z","timestamp":1631483157000},"page":"9841","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Evaluating Neuroprotective Effects of Uridine, Erythropoietin, and Therapeutic Hypothermia in a Ferret Model of Inflammation-Sensitized Hypoxic-Ischemic Encephalopathy"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2796-2184","authenticated-orcid":false,"given":"Kylie A.","family":"Corry","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia R.","family":"White","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AnnaMarie E.","family":"Shearlock","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Moralejo","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6279-1528","authenticated-orcid":false,"given":"Janessa B.","family":"Law","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6861-6229","authenticated-orcid":false,"given":"Sandra E.","family":"Juul","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"},{"name":"Center on Human Development and Disability, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Wood","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA"},{"name":"Center on Human Development and Disability, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,11]]},"reference":[{"key":"ref_1","first-page":"114","article-title":"Preterm Hypoxic-Ischemic Encephalopathy","volume":"4","author":"Gopagondanahalli","year":"2016","journal-title":"Front. Pediatrs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/pr.2013.206","article-title":"Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990","volume":"74","author":"Lee","year":"2013","journal-title":"Pediatr. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"103.e1","DOI":"10.1016\/j.ajog.2016.01.004","article-title":"Preterm neonatal morbidity and mortality by gestational age: A contemporary cohort","volume":"215","author":"Manuck","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/pch\/pxy028","article-title":"Hypothermia for newborns with hypoxic-ischemic encephalopathy","volume":"23","author":"Lemyre","year":"2018","journal-title":"Paediatr Child Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e1273","DOI":"10.1016\/S2214-109X(21)00264-3","article-title":"Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): A randomised controlled trial in India, Sri Lanka, and Bangladesh","volume":"9","author":"Thayyil","year":"2021","journal-title":"Lancet Glob. Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1203\/PDR.0b013e31818912d2","article-title":"White matter injury in term newborns with neonatal encephalopathy","volume":"65","author":"Li","year":"2009","journal-title":"Pediatr Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1159\/000498968","article-title":"A Ferret Model of Encephalopathy of Prematurity","volume":"40","author":"Wood","year":"2018","journal-title":"Dev. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"661759","DOI":"10.3389\/fcell.2021.661759","article-title":"The Ferret as a Model System for Neocortex Development and Evolution","volume":"9","author":"Gilardi","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ijdevneu.2018.05.006","article-title":"Ontogeny of white matter, toll-like receptor expression, and motor skills in the neonatal ferret","volume":"70","author":"Snyder","year":"2018","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.ijdevneu.2015.06.005","article-title":"Is the ferret a suitable species for studying perinatal brain injury?","volume":"45","author":"Empie","year":"2015","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_11","first-page":"e60131","article-title":"A Ferret Model of Inflammation-sensitized Late Preterm Hypoxic-ischemic Brain Injury","volume":"153","author":"Wood","year":"2019","journal-title":"J. Vis. Exp."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1203\/PDR.0b013e3181a291d9","article-title":"Characterization of brain development in the ferret via MRI","volume":"66","author":"Barnette","year":"2009","journal-title":"Pediatr. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1159\/000455838","article-title":"Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent","volume":"39","author":"Falck","year":"2017","journal-title":"Dev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.neulet.2013.02.035","article-title":"Neuroprotective effects of uridine in a rat model of neonatal hypoxic-ischemic encephalopathy","volume":"542","author":"Cansev","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/dmcn.13629","article-title":"Complex interactions between hypoxia-ischemia and inflammation in preterm brain injury","volume":"60","author":"Galinsky","year":"2018","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/nn.2553","article-title":"OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling","volume":"13","author":"Fietz","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1203\/PDR.0b013e31819d90c8","article-title":"Microarray analysis of high-dose recombinant erythropoietin treatment of unilateral brain injury in neonatal mouse hippocampus","volume":"65","author":"Juul","year":"2009","journal-title":"Pediatr. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.pediatrneurol.2014.06.008","article-title":"Erythropoietin: Emerging role of erythropoietin in neonatal neuroprotection","volume":"51","author":"Rangarajan","year":"2014","journal-title":"Pediatr. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1093\/cercor\/bhu066","article-title":"Postnatal Erythropoietin Mitigates Impaired Cerebral Cortical Development Following Subplate Loss from Prenatal Hypoxia-Ischemia","volume":"25","author":"Jantzie","year":"2015","journal-title":"Cereb. Cortex"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/pr.2013.155","article-title":"Erythropoietin signaling promotes oligodendrocyte development following prenatal systemic hypoxic-ischemic brain injury","volume":"74","author":"Jantzie","year":"2013","journal-title":"Pediatr. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1161\/01.STR.0000132196.49028.a4","article-title":"Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats","volume":"35","author":"Wang","year":"2004","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1523\/JNEUROSCI.4480-05.2006","article-title":"A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery","volume":"26","author":"Tsai","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.brainres.2017.09.010","article-title":"Uridine treatment protects against neonatal brain damage and long-term cognitive deficits caused by hyperoxia","volume":"1676","author":"Goren","year":"2017","journal-title":"Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.3906\/sag-2002-14","article-title":"Antioxidative effects of uridine in a neonatal rat model of hyperoxic brain injury","volume":"50","author":"Al","year":"2020","journal-title":"Turk. J. Med. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/BF00253962","article-title":"Uridine-induced hypothermia in mice and rats in relation to plasma and tissue levels of uridine and its metabolites","volume":"20","author":"Peters","year":"1987","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1152\/physrev.1992.72.2.449","article-title":"Erythropoietin: Structure, control of production, and function","volume":"72","author":"Jelkmann","year":"1992","journal-title":"Physiol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3181\/00379727-170-41394","article-title":"Erythropoietin elevation in the chronically hyperglycemic fetal lamb","volume":"170","author":"Philipps","year":"1982","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/0002-9378(89)90466-3","article-title":"Amniotic fluid erythropoietin predicts fetal distress in Rh-immunized pregnancies","volume":"160","author":"Voutilainen","year":"1989","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_29","first-page":"219","article-title":"Maternal alcohol abuse is associated with elevated fetal erythropoietin levels","volume":"76","author":"Halmesmaki","year":"1990","journal-title":"Obstet. Gynecol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ajog.2005.12.008","article-title":"Sources of amniotic fluid erythropoietin during normoxia and hypoxia in fetal sheep","volume":"195","author":"Brace","year":"2006","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1159\/000153094","article-title":"Increased fetal plasma and amniotic fluid erythropoietin concentrations: Markers of intrauterine hypoxia","volume":"95","author":"Teramo","year":"2009","journal-title":"Neonatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/pr.2012.139","article-title":"Hypothermia and erythropoietin for neuroprotection after neonatal brain damage","volume":"73","author":"Fan","year":"2013","journal-title":"Pediatr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/pr.2012.138","article-title":"Effects of combination therapy using hypothermia and erythropoietin in a rat model of neonatal hypoxia-ischemia","volume":"73","author":"Fang","year":"2013","journal-title":"Pediatr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1113\/JP279131","article-title":"Non-additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near-term fetal sheep","volume":"598","author":"Wassink","year":"2020","journal-title":"J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/pr.2012.148","article-title":"Hypothermia plus erythropoietin for neonatal neuroprotection? Commentary on Fan et al. and Fang et al","volume":"73","author":"Juul","year":"2013","journal-title":"Pediatr. Res."},{"key":"ref_36","first-page":"CD003311","article-title":"Cooling for newborns with hypoxic ischaemic encephalopathy","volume":"1","author":"Jacobs","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"c363","DOI":"10.1136\/bmj.c363","article-title":"Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: Synthesis and meta-analysis of trial data","volume":"340","author":"Edwards","year":"2010","journal-title":"BMJ"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1136\/bmj.317.7172.1549","article-title":"Antepartum risk factors for newborn encephalopathy: The Western Australian case-control study","volume":"317","author":"Badawi","year":"1998","journal-title":"BMJ"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1542\/peds.2012-0714","article-title":"Antecedents of neonatal encephalopathy in the Vermont Oxford Network Encephalopathy Registry","volume":"130","author":"Nelson","year":"2012","journal-title":"Pediatrics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1159\/000481980","article-title":"Neonatal Systemic Inflammation Induces Inflammatory Reactions and Brain Apoptosis in a Pathogen-Specific Manner","volume":"113","author":"Falck","year":"2018","journal-title":"Neonatology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Martinello, K.A., Meehan, C., Avdic-Belltheus, A., Lingam, I., Mutshiya, T., Yang, Q., Akin, M.A., Price, D., Sokolska, M., and Bainbridge, A. (2021). Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia-ischemia. Pediatr. Res., 1\u201312.","DOI":"10.1038\/s41390-021-01584-6"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.bbr.2004.09.003","article-title":"Time course of postnatal motor development in ferrets: Ontogenetic and comparative perspectives","volume":"158","author":"Christensson","year":"2005","journal-title":"Behav. Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113457","DOI":"10.1016\/j.expneurol.2020.113457","article-title":"Animal models for neonatal brain injury induced by hypoxic ischemic conditions in rodents","volume":"334","author":"Hamdy","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1056\/NEJMoa1907423","article-title":"A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants","volume":"382","author":"Juul","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s10863-016-9678-4","article-title":"Sex dependent alterations in mitochondrial electron transport chain proteins following neonatal rat cerebral hypoxic-ischemia","volume":"48","author":"Demarest","year":"2016","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/jnr.23828","article-title":"Sex-dependent consequences of neonatal brain hypoxia-ischemia in the rat","volume":"95","author":"Netto","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.expneurol.2014.01.003","article-title":"Sex differences in behavioral outcome following neonatal hypoxia ischemia: Insights from a clinical meta-analysis and a rodent model of induced hypoxic ischemic brain injury","volume":"254","author":"Smith","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1159\/000430860","article-title":"Hypothermia Does Not Reverse Cellular Responses Caused by Lipopolysaccharide in Neonatal Hypoxic-Ischaemic Brain Injury","volume":"37","author":"Osredkar","year":"2015","journal-title":"Dev. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1203\/01.PDR.0000169971.64558.5A","article-title":"Erythropoietin protects dopaminergic neurons and improves neurobehavioral outcomes in juvenile rats after neonatal hypoxia-ischemia","volume":"58","author":"Demers","year":"2005","journal-title":"Pediatr. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"FASEB J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/1423-0127-18-69","article-title":"Ceftriaxone attenuates hypoxic-ischemic brain injury in neonatal rats","volume":"18","author":"Lai","year":"2011","journal-title":"J. Biomed. Sci"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5670","DOI":"10.1007\/s12274-018-2104-y","article-title":"Curcumin-loaded polymeric nanoparticles for neuroprotection in neonatal rats with hypoxic-ischemic encephalopathy","volume":"11","author":"Joseph","year":"2018","journal-title":"Nano Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Riew, T.R., Shin, Y.J., Kim, H.L., Cho, J.M., Pak, H.J., and Lee, M.Y. (2016). Spatiotemporal Progression of Microcalcification in the Hippocampal CA1 Region following Transient Forebrain Ischemia in Rats: An Ultrastructural Study. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159229"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9841\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:01:05Z","timestamp":1760166065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9841"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,11]]},"references-count":53,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22189841"],"URL":"https:\/\/doi.org\/10.3390\/ijms22189841","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,11]]}}}