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Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning

Piel, Sarah ; Janowska, Joanna I. ; Ward, J. Laurenson ; McManus, Meagan J. ; Jose, Joshua S. ; Starr, Jonathan ; Sheldon, Malkah ; Clayman, Carly L. ; Elmér, Eskil LU orcid and Hansson, Magnus J. LU orcid , et al. (2022) In Scientific Reports 12(1).
Abstract

Pesticides account for hundreds of millions of cases of acute poisoning worldwide each year, with organophosphates (OPs) being responsible for the majority of all pesticide-related deaths. OPs inhibit the enzyme acetylcholinesterase (AChE), which leads to impairment of the central- and peripheral nervous system. Current standard of care (SOC) alleviates acute neurologic-, cardiovascular- and respiratory symptoms and reduces short term mortality. However, survivors often demonstrate significant neurologic sequelae. This highlights the critical need for further development of adjunctive therapies with novel targets. While the inhibition of AChE is thought to be the main mechanism of injury, mitochondrial dysfunction and resulting... (More)

Pesticides account for hundreds of millions of cases of acute poisoning worldwide each year, with organophosphates (OPs) being responsible for the majority of all pesticide-related deaths. OPs inhibit the enzyme acetylcholinesterase (AChE), which leads to impairment of the central- and peripheral nervous system. Current standard of care (SOC) alleviates acute neurologic-, cardiovascular- and respiratory symptoms and reduces short term mortality. However, survivors often demonstrate significant neurologic sequelae. This highlights the critical need for further development of adjunctive therapies with novel targets. While the inhibition of AChE is thought to be the main mechanism of injury, mitochondrial dysfunction and resulting metabolic crisis may contribute to the overall toxicity of these agents. We hypothesized that the mitochondrially targeted succinate prodrug NV354 would support mitochondrial function and reduce brain injury during acute intoxication with the OP diisopropylfluorophosphate (DFP). To this end, we developed a rat model of acute DFP intoxication and evaluated the efficacy of NV354 as adjunctive therapy to SOC treatment with atropine and pralidoxime. We demonstrate that NV354, in combination with atropine and pralidoxime therapy, significantly improved cerebral mitochondrial complex IV-linked respiration and reduced signs of brain injury in a rodent model of acute DFP exposure.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
12
issue
1
article number
20329
publisher
Nature Publishing Group
external identifiers
  • pmid:36434021
  • scopus:85142513478
ISSN
2045-2322
DOI
10.1038/s41598-022-24472-3
project
TCA cycle intermediates and mitochondrial reactive oxygen species
Mitochondrial dysfunction in drug and chemical toxicity: mechanism, target identification and therapeutic development
language
English
LU publication?
yes
id
cd2b59d6-4da8-4a31-9621-b8e07d54a396
date added to LUP
2022-12-20 15:31:13
date last changed
2024-04-18 16:48:50
@article{cd2b59d6-4da8-4a31-9621-b8e07d54a396,
  abstract     = {{<p>Pesticides account for hundreds of millions of cases of acute poisoning worldwide each year, with organophosphates (OPs) being responsible for the majority of all pesticide-related deaths. OPs inhibit the enzyme acetylcholinesterase (AChE), which leads to impairment of the central- and peripheral nervous system. Current standard of care (SOC) alleviates acute neurologic-, cardiovascular- and respiratory symptoms and reduces short term mortality. However, survivors often demonstrate significant neurologic sequelae. This highlights the critical need for further development of adjunctive therapies with novel targets. While the inhibition of AChE is thought to be the main mechanism of injury, mitochondrial dysfunction and resulting metabolic crisis may contribute to the overall toxicity of these agents. We hypothesized that the mitochondrially targeted succinate prodrug NV354 would support mitochondrial function and reduce brain injury during acute intoxication with the OP diisopropylfluorophosphate (DFP). To this end, we developed a rat model of acute DFP intoxication and evaluated the efficacy of NV354 as adjunctive therapy to SOC treatment with atropine and pralidoxime. We demonstrate that NV354, in combination with atropine and pralidoxime therapy, significantly improved cerebral mitochondrial complex IV-linked respiration and reduced signs of brain injury in a rodent model of acute DFP exposure.</p>}},
  author       = {{Piel, Sarah and Janowska, Joanna I. and Ward, J. Laurenson and McManus, Meagan J. and Jose, Joshua S. and Starr, Jonathan and Sheldon, Malkah and Clayman, Carly L. and Elmér, Eskil and Hansson, Magnus J. and Jang, David H. and Karlsson, Michael and Ehinger, Johannes K. and Kilbaugh, Todd J.}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning}},
  url          = {{http://dx.doi.org/10.1038/s41598-022-24472-3}},
  doi          = {{10.1038/s41598-022-24472-3}},
  volume       = {{12}},
  year         = {{2022}},
}