Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock

Abstract 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 su...

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Autores principales:	Kumar Subramani, Sumin Lu, Marie Warren, Xiaogang Chu, Haroldo A. Toque, R. William Caldwell, Michael P. Diamond, Raghavan Raju
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e822436faae34deb91a963d3534179b2
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spelling	oai:doaj.org-article:e822436faae34deb91a963d3534179b22021-12-02T16:06:37ZMitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock10.1038/s41598-017-02495-52045-2322https://doaj.org/article/e822436faae34deb91a963d3534179b22017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02495-5https://doaj.org/toc/2045-2322Abstract 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.Kumar SubramaniSumin LuMarie WarrenXiaogang ChuHaroldo A. ToqueR. William CaldwellMichael P. DiamondRaghavan RajuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kumar Subramani Sumin Lu Marie Warren Xiaogang Chu Haroldo A. Toque R. William Caldwell Michael P. Diamond Raghavan Raju Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
description	Abstract 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.
format	article
author	Kumar Subramani Sumin Lu Marie Warren Xiaogang Chu Haroldo A. Toque R. William Caldwell Michael P. Diamond Raghavan Raju
author_facet	Kumar Subramani Sumin Lu Marie Warren Xiaogang Chu Haroldo A. Toque R. William Caldwell Michael P. Diamond Raghavan Raju
author_sort	Kumar Subramani
title	Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
title_short	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_sort	mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e822436faae34deb91a963d3534179b2
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Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock

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