Abstract
The aim of this study was to test the effect of a small volume administration of p-hydroxyphenylpyruvate (pHPP) in a rat model of profound hemorrhagic shock and to assess a possible metabolic mechanism of action of the compound. The results obtained show that hemorrhaged rats treated with 2–4% of the estimated blood volume of pHPP survived significantly longer (p<0.001) than rats treated with vehicle. In vitro analysis on cultured EA.hy 926 cells demonstrated that pHPP improved cell growth rate and promoted cell survival under stressing conditions. Moreover, pHPP stimulated mitochondria-related respiration under ATP-synthesizing conditions and exhibited antioxidant activity toward mitochondria-generated reactive oxygen species. The compound effects reported in the in vitro and in vivo analyses were obtained in the same millimolar concentration range. These data disclose pHPP as an efficient energetic substrates-supplier to the mitochondrial respiratory chain as well as an antioxidant supporting the view that the compound warrants further evaluation as a therapeutic agent.
Highlights
Trauma death is a leading cause of death throughout the world [1]
It shows that all animals survived at least 1 h following the initiation of hemorrhage
Five of 12 animals treated with pHPP survived longer than 4 h and 1 rat survived for 455 min
Summary
Trauma death is a leading cause of death throughout the world [1]. The most common cause of death in polytrauma patients is hemorrhagic shock (HS). Hemorrhage leads to reduced tissue perfusion and, if prolonged, irreversible cell damage caused by depletion of substrate availability, [2,3]. Standard management for HS consists of the intravenous administraton of adequate volumes of sanguinous and asanguinous fluids [4]. Administration of large volumes of resuscitation fluids can be associated with increased blood loss, exacerbation of acute lung injury and high mortality [5,6]. Investigators have been interested in developing therapeutic approaches, which can prolong survival of patients with HS without requiring the administration of a large volume of resuscitation fluid
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