title: 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.
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.
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Cotoia
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Scrima
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Gefter
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Piccoli
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Cinnella
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Dambrosio
authors.affiliation: Department of Surgery and Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Fink
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Capitanio
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010649:Phenylalanine / Q000378:metabolism*; D010667:Phenylpyruvic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D013312:Stress, Physiological / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D016019:Survival Analysis; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D010667:Phenylpyruvic Acids; D017382:Reactive Oxygen Species; D013481:Superoxides; C010590:4-hydroxyphenylpyruvic acid; D014443:Tyrosine; D010649:Phenylalanine