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Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning

Alomaja, Oladunni ; Shofer, Frances S. ; Greenwood, John C. ; Piel, Sarah ; Clayman, Carly ; Mesaros, Clementina ; Kao, Shih Han ; Shin, Samuel S. ; Ehinger, Johannes K. LU orcid and Kilbaugh, Todd J. , et al. (2023) In Journal of Medical Toxicology 19(2). p.196-204
Abstract

Introduction: Cyanide exposure can occur in various settings such as industry and metallurgy. The primary mechanism of injury is cellular hypoxia from Complex IV (CIV) inhibition. This leads to decreased ATP production and increased reactive oxygen species production. The brain and the heart are the organs most affected due to their high metabolic demand. While the cardiac effects of cyanide are well known, the cerebral effects on cellular function are less well described. We investigated cerebral metabolism with a combination of brain respirometry, microdialysis, and western blotting using a rodent model of sub-lethal cyanide poisoning. Methods: Twenty rodents were divided into two groups: control (n = 10) and sub-lethal cyanide (n =... (More)

Introduction: Cyanide exposure can occur in various settings such as industry and metallurgy. The primary mechanism of injury is cellular hypoxia from Complex IV (CIV) inhibition. This leads to decreased ATP production and increased reactive oxygen species production. The brain and the heart are the organs most affected due to their high metabolic demand. While the cardiac effects of cyanide are well known, the cerebral effects on cellular function are less well described. We investigated cerebral metabolism with a combination of brain respirometry, microdialysis, and western blotting using a rodent model of sub-lethal cyanide poisoning. Methods: Twenty rodents were divided into two groups: control (n = 10) and sub-lethal cyanide (n = 10). Cerebral microdialysis was performed during a 2 mg/kg/h cyanide exposure to obtain real-time measurements of cerebral metabolic status. At the end of the exposure (90 min), brain-isolated mitochondria were measured for mitochondrial respiration. Brain tissue ATP concentrations, acyl-Coenzyme A thioesters, and mitochondrial content were also measured. Results: The cyanide group showed significantly increased lactate and decreased hypotension with decreased cerebral CIV-linked mitochondrial respiration. There was also a significant decrease in cerebral ATP concentration in the cyanide group and a significantly higher cerebral lactate-to-pyruvate ratio (LPR). In addition, we also found decreased expression of Complex III and IV protein expression in brain tissue from the cyanide group. Finally, there was no change in acyl-coenzyme A thioesters between the two groups. Conclusions: The key finding demonstrates mitochondrial dysfunction in brain tissue that corresponds with a decrease in mitochondrial function, ATP concentrations, and an elevated LPR indicating brain dysfunction at a sub-lethal dose of cyanide.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Basic science, Cerebral metabolism, Cyanide, Mitochondria
in
Journal of Medical Toxicology
volume
19
issue
2
pages
196 - 204
publisher
Springer
external identifiers
  • scopus:85147744213
  • pmid:36757579
ISSN
1556-9039
DOI
10.1007/s13181-022-00928-w
project
Mitochondrial dysfunction in drug and chemical toxicity: mechanism, target identification and therapeutic development
language
English
LU publication?
yes
id
9d363a88-1428-4d4e-a85d-7a56e0c6814f
date added to LUP
2023-02-23 15:43:52
date last changed
2024-06-14 00:13:18
@article{9d363a88-1428-4d4e-a85d-7a56e0c6814f,
  abstract     = {{<p>Introduction: Cyanide exposure can occur in various settings such as industry and metallurgy. The primary mechanism of injury is cellular hypoxia from Complex IV (CIV) inhibition. This leads to decreased ATP production and increased reactive oxygen species production. The brain and the heart are the organs most affected due to their high metabolic demand. While the cardiac effects of cyanide are well known, the cerebral effects on cellular function are less well described. We investigated cerebral metabolism with a combination of brain respirometry, microdialysis, and western blotting using a rodent model of sub-lethal cyanide poisoning. Methods: Twenty rodents were divided into two groups: control (n = 10) and sub-lethal cyanide (n = 10). Cerebral microdialysis was performed during a 2 mg/kg/h cyanide exposure to obtain real-time measurements of cerebral metabolic status. At the end of the exposure (90 min), brain-isolated mitochondria were measured for mitochondrial respiration. Brain tissue ATP concentrations, acyl-Coenzyme A thioesters, and mitochondrial content were also measured. Results: The cyanide group showed significantly increased lactate and decreased hypotension with decreased cerebral CIV-linked mitochondrial respiration. There was also a significant decrease in cerebral ATP concentration in the cyanide group and a significantly higher cerebral lactate-to-pyruvate ratio (LPR). In addition, we also found decreased expression of Complex III and IV protein expression in brain tissue from the cyanide group. Finally, there was no change in acyl-coenzyme A thioesters between the two groups. Conclusions: The key finding demonstrates mitochondrial dysfunction in brain tissue that corresponds with a decrease in mitochondrial function, ATP concentrations, and an elevated LPR indicating brain dysfunction at a sub-lethal dose of cyanide.</p>}},
  author       = {{Alomaja, Oladunni and Shofer, Frances S. and Greenwood, John C. and Piel, Sarah and Clayman, Carly and Mesaros, Clementina and Kao, Shih Han and Shin, Samuel S. and Ehinger, Johannes K. and Kilbaugh, Todd J. and Jang, David H.}},
  issn         = {{1556-9039}},
  keywords     = {{Basic science; Cerebral metabolism; Cyanide; Mitochondria}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{196--204}},
  publisher    = {{Springer}},
  series       = {{Journal of Medical Toxicology}},
  title        = {{Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning}},
  url          = {{http://dx.doi.org/10.1007/s13181-022-00928-w}},
  doi          = {{10.1007/s13181-022-00928-w}},
  volume       = {{19}},
  year         = {{2023}},
}