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Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model

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...

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Autores principales: Kumar, Parvathi, Hair, Pamela, Cunnion, Kenji, Krishna, Neel, Bass, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483388/
https://www.ncbi.nlm.nih.gov/pubmed/34591905
http://dx.doi.org/10.1371/journal.pone.0257960
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author Kumar, Parvathi
Hair, Pamela
Cunnion, Kenji
Krishna, Neel
Bass, Thomas
author_facet Kumar, Parvathi
Hair, Pamela
Cunnion, Kenji
Krishna, Neel
Bass, Thomas
author_sort Kumar, Parvathi
collection PubMed
description 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<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<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.
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spelling pubmed-84833882021-10-01 Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model Kumar, Parvathi Hair, Pamela Cunnion, Kenji Krishna, Neel Bass, Thomas PLoS One Research Article 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<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<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. Public Library of Science 2021-09-30 /pmc/articles/PMC8483388/ /pubmed/34591905 http://dx.doi.org/10.1371/journal.pone.0257960 Text en © 2021 Kumar et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kumar, Parvathi
Hair, Pamela
Cunnion, Kenji
Krishna, Neel
Bass, Thomas
Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model
title Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model
title_full Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model
title_fullStr Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model
title_full_unstemmed Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model
title_short Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model
title_sort classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483388/
https://www.ncbi.nlm.nih.gov/pubmed/34591905
http://dx.doi.org/10.1371/journal.pone.0257960
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