p-Hydroxyphenylpyruvate, an intermediate of the Phe/Tyr catabolism, improves mitochondrial oxidative metabolism under stressing conditions and prolongs survival in rats subjected to profound hemorrhagic shock

Antonella Cotoia; Rosella Scrima; Julia V Gefter; Claudia Piccoli; Gilda Cinnella; Michele Dambrosio; Mitchell P Fink; Nazzareno Capitanio

doi:10.1371/journal.pone.0090917

p-Hydroxyphenylpyruvate, an intermediate of the Phe/Tyr catabolism, improves mitochondrial oxidative metabolism under stressing conditions and prolongs survival in rats subjected to profound hemorrhagic shock

PLoS One. 2014 Mar 5;9(3):e90917. doi: 10.1371/journal.pone.0090917. eCollection 2014.

Authors

Antonella Cotoia¹, Rosella Scrima², Julia V Gefter³, Claudia Piccoli², Gilda Cinnella¹, Michele Dambrosio¹, Mitchell P Fink⁴, Nazzareno Capitanio²

Affiliations

¹ Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
² Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
³ Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
⁴ Department of Surgery and Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Proliferation / drug effects
Cell Respiration / drug effects
Cell Survival / drug effects
Hemodynamics / drug effects
Humans
Metabolic Networks and Pathways / drug effects
Mitochondria / drug effects
Mitochondria / metabolism*
Oxidation-Reduction
Phenylalanine / metabolism*
Phenylpyruvic Acids / pharmacology
Phenylpyruvic Acids / therapeutic use*
Rats
Reactive Oxygen Species / metabolism
Shock, Hemorrhagic / chemically induced
Shock, Hemorrhagic / drug therapy*
Shock, Hemorrhagic / metabolism*
Shock, Hemorrhagic / physiopathology
Stress, Physiological* / drug effects
Subcellular Fractions / drug effects
Subcellular Fractions / metabolism
Superoxides / metabolism
Survival Analysis
Tyrosine / metabolism*

Substances

Phenylpyruvic Acids
Reactive Oxygen Species
Superoxides
4-hydroxyphenylpyruvic acid
Tyrosine
Phenylalanine

Grants and funding

This study was financed by Defense Advanced Research Projects Agency (DARPA), University of Pittsburgh, USA, and by local grants of the Departments of Anesthesiology and Clinical and Experimental Medicine, University of Foggia, Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.