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The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury

Following traumatic brain injury (TBI) neurological damage is ongoing through a complex cascade of primary and secondary injury events in the ensuing minutes, days and weeks. The delayed nature of secondary injury provides a valuable window of opportunity to limit the consequences with a timely trea...

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Autores principales: Plummer, Stephanie L., Corrigan, Frances, Thornton, Emma, Woenig, Joshua A., Vink, Robert, Cappai, Roberto, Van Den Heuvel, Corinna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761886/
https://www.ncbi.nlm.nih.gov/pubmed/29320530
http://dx.doi.org/10.1371/journal.pone.0190449
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author Plummer, Stephanie L.
Corrigan, Frances
Thornton, Emma
Woenig, Joshua A.
Vink, Robert
Cappai, Roberto
Van Den Heuvel, Corinna
author_facet Plummer, Stephanie L.
Corrigan, Frances
Thornton, Emma
Woenig, Joshua A.
Vink, Robert
Cappai, Roberto
Van Den Heuvel, Corinna
author_sort Plummer, Stephanie L.
collection PubMed
description Following traumatic brain injury (TBI) neurological damage is ongoing through a complex cascade of primary and secondary injury events in the ensuing minutes, days and weeks. The delayed nature of secondary injury provides a valuable window of opportunity to limit the consequences with a timely treatment. Recently, the amyloid precursor protein (APP) and its derivative APP96-110 have shown encouraging neuroprotective activity following TBI following an intracerebroventricular administration. Nevertheless, its broader clinical utility would be enhanced by an intravenous (IV) administration. This study assessed the efficacy of IV APP96-110, where a dose-response for a single dose of 0.005mg/kg– 0.5mg/kg APP96-110 at either 30 minutes or 5 hours following moderate-severe diffuse impact-acceleration injury was performed. Male Sprague-Dawley rats were assessed daily for 3 or 7 days on the rotarod to examine motor outcome, with a separate cohort of animals utilised for immunohistochemistry analysis 3 days post-TBI to assess axonal injury and neuroinflammation. Animals treated with 0.05mg/kg or 0.5mg/kg APP96-110 after 30 minutes demonstrated significant improvements in motor outcome. This was accompanied by a reduction in axonal injury and neuroinflammation in the corpus callosum at 3 days post-TBI, whereas 0.005mg/kg had no effect. In contrast, treatment with 0.005m/kg or 0.5mg/kg APP96-110 at 5 hours post-TBI demonstrated significant improvements in motor outcome over 3 days, which was accompanied by a reduction in axonal injury in the corpus callosum. This demonstrates that APP96-110 remains efficacious for up to 5 hours post-TBI when administered IV, and supports its development as a novel therapeutic compound following TBI.
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spelling pubmed-57618862018-01-23 The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury Plummer, Stephanie L. Corrigan, Frances Thornton, Emma Woenig, Joshua A. Vink, Robert Cappai, Roberto Van Den Heuvel, Corinna PLoS One Research Article Following traumatic brain injury (TBI) neurological damage is ongoing through a complex cascade of primary and secondary injury events in the ensuing minutes, days and weeks. The delayed nature of secondary injury provides a valuable window of opportunity to limit the consequences with a timely treatment. Recently, the amyloid precursor protein (APP) and its derivative APP96-110 have shown encouraging neuroprotective activity following TBI following an intracerebroventricular administration. Nevertheless, its broader clinical utility would be enhanced by an intravenous (IV) administration. This study assessed the efficacy of IV APP96-110, where a dose-response for a single dose of 0.005mg/kg– 0.5mg/kg APP96-110 at either 30 minutes or 5 hours following moderate-severe diffuse impact-acceleration injury was performed. Male Sprague-Dawley rats were assessed daily for 3 or 7 days on the rotarod to examine motor outcome, with a separate cohort of animals utilised for immunohistochemistry analysis 3 days post-TBI to assess axonal injury and neuroinflammation. Animals treated with 0.05mg/kg or 0.5mg/kg APP96-110 after 30 minutes demonstrated significant improvements in motor outcome. This was accompanied by a reduction in axonal injury and neuroinflammation in the corpus callosum at 3 days post-TBI, whereas 0.005mg/kg had no effect. In contrast, treatment with 0.005m/kg or 0.5mg/kg APP96-110 at 5 hours post-TBI demonstrated significant improvements in motor outcome over 3 days, which was accompanied by a reduction in axonal injury in the corpus callosum. This demonstrates that APP96-110 remains efficacious for up to 5 hours post-TBI when administered IV, and supports its development as a novel therapeutic compound following TBI. Public Library of Science 2018-01-10 /pmc/articles/PMC5761886/ /pubmed/29320530 http://dx.doi.org/10.1371/journal.pone.0190449 Text en © 2018 Plummer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://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
Plummer, Stephanie L.
Corrigan, Frances
Thornton, Emma
Woenig, Joshua A.
Vink, Robert
Cappai, Roberto
Van Den Heuvel, Corinna
The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury
title The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury
title_full The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury
title_fullStr The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury
title_full_unstemmed The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury
title_short The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury
title_sort amyloid precursor protein derivative, app96-110, is efficacious following intravenous administration after traumatic brain injury
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761886/
https://www.ncbi.nlm.nih.gov/pubmed/29320530
http://dx.doi.org/10.1371/journal.pone.0190449
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