{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:11:39Z","timestamp":1785499899900,"version":"3.56.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Perinatal hypoxic ischemic encephalopathy (HIE) remains a major contributor of infant death and long-term disability worldwide. The role played by the complement system in this ischemia-reperfusion injury remains poorly understood. In order to better understand the role of complement activation and other modifiable mechanisms of injury in HIE, we tested the dual-targeting anti-inflammatory peptide, RLS-0071 in an animal model of HIE. Using the well-established HIE rat pup model we measured the effects of RLS-0071 during the acute stages of the brain injury and on long-term neurocognitive outcomes. Rat pups subject to hypoxia-ischemia insult received one of 4 interventions including normothermia, hypothermia and RLS-0071 with and without hypothermia. We measured histopathological effects, brain C1q levels and neuroimaging at day 1 and 21 after the injury. A subset of animals was followed into adolescence and evaluated for neurocognitive function. On histological evaluation, RLS-0071 showed neuronal protection in combination with hypothermia (P = 0.048) in addition to reducing C1q levels in the brain at 1hr (P = 0.01) and at 8 hr in combination with hypothermia (P = 0.005). MRI neuroimaging demonstrated that RLS-0071 in combination with hypothermia reduced lesion volume at 24 hours (P&lt;0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P&lt;0.01). RLS-0071 alone or in combination with hypothermia improved both short-term and long-term memory. These findings suggest that modulation by RLS-0071 can potentially decrease brain damage resulting from HIE.<\/jats:p>","DOI":"10.1371\/journal.pone.0257960","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T18:56:35Z","timestamp":1633028195000},"page":"e0257960","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5769-7086","authenticated-orcid":true,"given":"Parvathi","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Hair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Cunnion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neel","family":"Krishna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"issue":"6","key":"pone.0257960.ref001","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.earlhumdev.2010.05.010","article-title":"Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy","volume":"86","author":"JJ Kurinczuk","year":"2010","journal-title":"Early Hum Dev"},{"key":"pone.0257960.ref002","first-page":"Cd003311","article-title":"Cooling for newborns with hypoxic ischaemic encephalopathy","volume":"1","author":"SE Jacobs","year":"2013","journal-title":"The Cochrane database of systematic reviews"},{"issue":"4","key":"pone.0257960.ref003","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.clp.2012.09.008","article-title":"Hypoxic-ischemic encephalopathy and novel strategies for neuroprotection","volume":"39","author":"S. 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encephalopathy","volume":"109","author":"G Dixon","year":"2002","journal-title":"Pediatrics"},{"issue":"1","key":"pone.0257960.ref034","doi-asserted-by":"crossref","first-page":"67","DOI":"10.5409\/wjcp.v5.i1.67","article-title":"Short and long term prognosis in perinatal asphyxia: An update","volume":"5","author":"CE Ahearne","year":"2016","journal-title":"World J Clin Pediatr"},{"issue":"3","key":"pone.0257960.ref035","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/brain\/123.3.499","article-title":"Developmental amnesia associated with early hypoxic\u2013ischaemic injury","volume":"123","author":"DG Gadian","year":"2000","journal-title":"Brain"},{"issue":"5","key":"pone.0257960.ref036","doi-asserted-by":"crossref","first-page":"F380","DOI":"10.1136\/adc.2004.067520","article-title":"Neuropsychological and educational problems at school age associated with neonatal encephalopathy","volume":"90","author":"N Marlow","year":"2005","journal-title":"Archives of Disease in 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