Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number2653
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Hemorrhagic Shock
Resuscitation
AMP-Activated Protein Kinases
Wounds and Injuries
Orphan Drug Production
Therapeutics
Mitochondrial Membrane Potential
Metabolic Networks and Pathways
Blood Volume
Blood Vessels
Cause of Death
Lactic Acid
Mitochondria
Animal Models
Adenosine Triphosphate
Membranes

ASJC Scopus subject areas

  • General

Cite this

Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock. / Subramani, Kumar; Lu, Sumin; Warren, Marie; Chu, Xiaogang; Flores Toque, Haroldo Alfredo; Caldwell, Robert William; Diamond, Michael Peter; Raju, Raghavan Pillai.

In: Scientific Reports, Vol. 7, No. 1, 2653, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Caldwell, Robert William

AU - Diamond, Michael Peter

AU - Raju, Raghavan Pillai

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