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

↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Search: onr:"swepub:oai:lup.lub.lu.se:e5fa13c1-fe9b-4605-a0e9-fe9926fcc8ab" > Succinate prodrugs ...

1 of 1
Previous record
Next record
To hitlist

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

Piel, Sarah (author): The Children's Hospital of Philadelphia

Janowska, Joanna I. (author): The Children's Hospital of Philadelphia

Ward, J. Laurenson (author): The Children's Hospital of Philadelphia

McManus, Meagan J. (author): The Children's Hospital of Philadelphia

Aronowitz, Danielle I. (author): The Children's Hospital of Philadelphia

Janowski, Piotr K. (author): The Children's Hospital of Philadelphia

Starr, Jonathan (author): The Children's Hospital of Philadelphia

Hook, Jordan N. (author): University of Iowa Carver College of Medicine

Hefti, Marco M. (author): University of Iowa Carver College of Medicine

Clayman, Carly L. (author): The Children's Hospital of Philadelphia

Elmér, Eskil (author): Lund University,Lunds universitet,Klinisk neurofysiologi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Clinical Neurophysiology,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Mitochondrial Medicine,Lund University Research Groups,Abliva AB

Hansson, Magnus J. (author): Lund University,Lunds universitet,Klinisk neurofysiologi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Clinical Neurophysiology,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Mitochondrial Medicine,Lund University Research Groups,Abliva AB

Jang, David H. (author): University of Pennsylvania

Karlsson, Michael (author): Copenhagen University Hospital

Ehinger, Johannes K. (author): Lund University,Lunds universitet,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Mitochondrial Medicine,Lund University Research Groups

Kilbaugh, Todd J. (author): The Children's Hospital of Philadelphia

show less...

(creator_code:org_t)

2022-10-25
2023
English.
In: Molecular and Cellular Biochemistry. - : Springer Science and Business Media LLC. - 0300-8177 .- 1573-4919. ; 478:6, s. 1231-1244

Related links:: http://dx.doi.org/10...; show more...; https://lup.lub.lu.s...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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 (OXPHOSCI) (− 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.

Find in a library

Molecular and Cellular Biochemistry (Search for host publication in LIBRIS)

To the university's database

1 of 1
Previous record
Next record
To hitlist

Find more in SwePub

By the author/editor: Piel, Sarah; Janowska, Joanna ...; Ward, J. Laurens ...; McManus, Meagan ...; Aronowitz, Danie ...; Janowski, Piotr ...; show more...; Starr, Jonathan; Hook, Jordan N.; Hefti, Marco M.; Clayman, Carly L ...; Elmér, Eskil; Hansson, Magnus ...; Jang, David H.; Karlsson, Michae ...; Ehinger, Johanne ...; Kilbaugh, Todd J ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmacology and ...

Articles in the publication: Molecular and Ce ...

By the university: Lund University

Search outside SwePub

Extend your search to:: Google; Google Book Search; Google Scholar

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se

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

Subject headings

Keyword

Publication and Content Type

Find in a library

To the university's database

Find more in SwePub

Search outside SwePub