Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.

Autor: Piel S; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA. piels@chop.edu.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA. piels@chop.edu., Janowska JI; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA., Ward JL; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA., McManus MJ; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA., Aronowitz DI; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA., Janowski PK; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA., Starr J; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA., Hook JN; Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, USA., Hefti MM; Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, USA., Clayman CL; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA., Elmér E; Abliva AB, Lund, Sweden.; Mitochondrial Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Hansson MJ; Abliva AB, Lund, Sweden.; Mitochondrial Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Jang DH; Department of Emergency Medicine, Division of Medical Toxicology, University of Pennsylvania School of Medicine, Philadelphia, USA., Karlsson M; Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark., Ehinger JK; Mitochondrial Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.; Otorhinolaryngology, Head and Neck Surgery, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden., Kilbaugh TJ; Resuscitation Science Center of Emphasis, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.; Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, USA.
Jazyk: angličtina
Zdroj: Molecular and cellular biochemistry [Mol Cell Biochem] 2023 Jun; Vol. 478 (6), pp. 1231-1244. Date of Electronic Publication: 2022 Oct 25.
DOI: 10.1007/s11010-022-04589-9
Abstrakt: Sodium fluoroacetate (FA) is a metabolic poison that systemically inhibits the tricarboxylic acid (TCA) cycle, causing energy deficiency and ultimately multi-organ failure. It poses a significant threat to society because of its high toxicity, potential use as a chemical weapon and lack of effective antidotal therapy. In this study, we investigated cell-permeable succinate prodrugs as potential treatment for acute FA intoxication. We hypothesized that succinate prodrugs would bypass FA-induced mitochondrial dysfunction, provide metabolic support, and prevent metabolic crisis during acute FA intoxication. To test this hypothesis, rats were exposed to FA (0.75 mg/kg) and treated with the succinate prodrug candidate NV354. Treatment efficacy was evaluated based on cardiac and cerebral mitochondrial respiration, mitochondrial content, metabolic profiles and tissue pathology. In the heart, FA increased concentrations of the TCA metabolite citrate (+ 4.2-fold, p < 0.01) and lowered ATP levels (- 1.9-fold, p < 0.001), confirming the inhibition of the TCA cycle by FA. High-resolution respirometry of cardiac mitochondria further revealed an impairment of mitochondrial complex V (CV)-linked metabolism, as evident by a reduced phosphorylation system control ratio (- 41%, p < 0.05). The inhibition of CV-linked metabolism is a novel mechanism of FA cardiac toxicity, which has implications for drug development and which NV354 was unable to counteract at the given dose. In the brain, FA induced the accumulation of β-hydroxybutyrate (+ 1.4-fold, p < 0.05) and the reduction of mitochondrial complex I (CI)-linked oxidative phosphorylation (OXPHOS CI ) (- 20%, p < 0.01), the latter of which was successfully alleviated by NV354. This promising effect of NV354 warrants further investigations to determine its potential neuroprotective effects.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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