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Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock

Hemorrhagic shock is a leading cause of death in people under the age of 45 and accounts for almost half of trauma-related deaths. In order to develop a treatment strategy based on potentiating mitochondrial function, we investigated the effect of the orphan drug dichloroacetate (DCA) on survival in...

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Autores principales: Subramani, Kumar, Lu, Sumin, Warren, Marie, Chu, Xiaogang, Toque, Haroldo A., Caldwell, R. William, Diamond, Michael P., Raju, Raghavan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453974/
https://www.ncbi.nlm.nih.gov/pubmed/28572638
http://dx.doi.org/10.1038/s41598-017-02495-5
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author Subramani, Kumar
Lu, Sumin
Warren, Marie
Chu, Xiaogang
Toque, Haroldo A.
Caldwell, R. William
Diamond, Michael P.
Raju, Raghavan
author_facet Subramani, Kumar
Lu, Sumin
Warren, Marie
Chu, Xiaogang
Toque, Haroldo A.
Caldwell, R. William
Diamond, Michael P.
Raju, Raghavan
author_sort Subramani, Kumar
collection PubMed
description Hemorrhagic shock is a leading cause of death in people under the age of 45 and accounts for almost half of trauma-related deaths. In order to develop a treatment strategy based on potentiating mitochondrial function, we investigated the effect of the orphan drug dichloroacetate (DCA) on survival in an animal model of hemorrhagic shock in the absence of fluid resuscitation. Hemorrhagic shock was induced in rats by withdrawing 60% of the blood volume and maintaining a hypotensive state. The studies demonstrated prolonged survival of rats subjected to hemorrhagic injury (HI) when treated with DCA. In separate experiments, using a fluid resuscitation model we studied mitochondrial functional alterations and changes in metabolic networks connected to mitochondria following HI and treatment with DCA. DCA treatment restored cardiac mitochondrial membrane potential and tissue ATP in the rats following HI. Treatment with DCA resulted in normalization of several metabolic and molecular parameters including plasma lactate and p-AMPK/AMPK, as well as Ach-mediated vascular relaxation. In conclusion we demonstrate that DCA can be successfully used in the treatment of hemorrhagic shock in the absence of fluid resuscitation; therefore DCA may be a good candidate in prolonged field care following severe blood loss.
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spelling pubmed-54539742017-06-06 Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock Subramani, Kumar Lu, Sumin Warren, Marie Chu, Xiaogang Toque, Haroldo A. Caldwell, R. William Diamond, Michael P. Raju, Raghavan Sci Rep Article Hemorrhagic shock is a leading cause of death in people under the age of 45 and accounts for almost half of trauma-related deaths. In order to develop a treatment strategy based on potentiating mitochondrial function, we investigated the effect of the orphan drug dichloroacetate (DCA) on survival in an animal model of hemorrhagic shock in the absence of fluid resuscitation. Hemorrhagic shock was induced in rats by withdrawing 60% of the blood volume and maintaining a hypotensive state. The studies demonstrated prolonged survival of rats subjected to hemorrhagic injury (HI) when treated with DCA. In separate experiments, using a fluid resuscitation model we studied mitochondrial functional alterations and changes in metabolic networks connected to mitochondria following HI and treatment with DCA. DCA treatment restored cardiac mitochondrial membrane potential and tissue ATP in the rats following HI. Treatment with DCA resulted in normalization of several metabolic and molecular parameters including plasma lactate and p-AMPK/AMPK, as well as Ach-mediated vascular relaxation. In conclusion we demonstrate that DCA can be successfully used in the treatment of hemorrhagic shock in the absence of fluid resuscitation; therefore DCA may be a good candidate in prolonged field care following severe blood loss. Nature Publishing Group UK 2017-06-01 /pmc/articles/PMC5453974/ /pubmed/28572638 http://dx.doi.org/10.1038/s41598-017-02495-5 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Subramani, Kumar
Lu, Sumin
Warren, Marie
Chu, Xiaogang
Toque, Haroldo A.
Caldwell, R. William
Diamond, Michael P.
Raju, Raghavan
Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
title Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
title_full Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
title_fullStr Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
title_full_unstemmed Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
title_short Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
title_sort mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453974/
https://www.ncbi.nlm.nih.gov/pubmed/28572638
http://dx.doi.org/10.1038/s41598-017-02495-5
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