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In vitro comparison of hydroxocobalamin (B12a) and the mitochondrial directed therapy by a succinate prodrug in a cellular model of cyanide poisoning

Owiredu, Shawn ; Ranganathan, Abhay ; Greenwood, John C ; Piel, Sarah LU orcid ; Janowska, Joanna I ; Eckmann, David M ; Kelly, Matthew ; Ehinger, Johannes K LU orcid ; Kilbaugh, Todd J and Jang, David H (2020) In Toxicology Reports 7. p.1263-1271
Abstract

The objective of this study was to compare the use of hydroxocobalamin (B12a) and a succinate prodrug to evaluate for improvement in mitochondrial function in an in vitro model of cyanide poisoning. Peripheral blood mononuclear cells (PBMC) and human aortic smooth muscle cells (HASMC) incubated with 50 mM of sodium cyanide (CN) for five minutes serving as the CN group compared to controls. We investigated the following: (1) Mitochondrial respiration; (2) Superoxide and mitochondrial membrane potential with microscopy; (3) Citrate synthase protein expression. All experiments were performed with a cell concentration of 2-3 × 106 cells/ml for both PBMC and HASMC. There were four conditions: (1) Control (no exposure); (2) Cyanide (exposure... (More)

The objective of this study was to compare the use of hydroxocobalamin (B12a) and a succinate prodrug to evaluate for improvement in mitochondrial function in an in vitro model of cyanide poisoning. Peripheral blood mononuclear cells (PBMC) and human aortic smooth muscle cells (HASMC) incubated with 50 mM of sodium cyanide (CN) for five minutes serving as the CN group compared to controls. We investigated the following: (1) Mitochondrial respiration; (2) Superoxide and mitochondrial membrane potential with microscopy; (3) Citrate synthase protein expression. All experiments were performed with a cell concentration of 2-3 × 106 cells/ml for both PBMC and HASMC. There were four conditions: (1) Control (no exposure); (2) Cyanide (exposure only); (3) B12a (cyanide exposure followed by B12a treatment); (4) NV118 (cyanide followed by NV118 treatment). In this study the key findings include: (1) Improvement in key mitochondrial respiratory states with the succinate prodrug (NV118) but not B12a; (2) Attenuation of superoxide production with treatment of NV118 but not with B12a treatment; (3) The changes in respiration were not secondary to increased mitochondrial content as measured by citrate synthase; (4) The use of easily accessible human blood cells showed similar mitochondrial response to both cyanide and treatment to HASMC. The use of a succinate prodrug to circumvent partial CIV inhibition by cyanide with clear reversal of cellular respiration and superoxide production that was not attributed to changes in mitochondrial content not seen by the use of B12a.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Respiration, Cyanide, Mitochondria, Antidote
in
Toxicology Reports
volume
7
pages
9 pages
publisher
Elsevier
external identifiers
  • scopus:85091089027
  • pmid:33005568
ISSN
2214-7500
DOI
10.1016/j.toxrep.2020.09.002
project
Mitochondrial dysfunction in drug and chemical toxicity: mechanism, target identification and therapeutic development
language
English
LU publication?
no
additional info
© 2020 Published by Elsevier B.V.
id
f78bd3e8-d58c-4a0e-ab29-ff7d5539b5da
date added to LUP
2023-08-11 10:28:55
date last changed
2024-03-22 23:05:37
@article{f78bd3e8-d58c-4a0e-ab29-ff7d5539b5da,
  abstract     = {{<p>The objective of this study was to compare the use of hydroxocobalamin (B12a) and a succinate prodrug to evaluate for improvement in mitochondrial function in an in vitro model of cyanide poisoning. Peripheral blood mononuclear cells (PBMC) and human aortic smooth muscle cells (HASMC) incubated with 50 mM of sodium cyanide (CN) for five minutes serving as the CN group compared to controls. We investigated the following: (1) Mitochondrial respiration; (2) Superoxide and mitochondrial membrane potential with microscopy; (3) Citrate synthase protein expression. All experiments were performed with a cell concentration of 2-3 × 106 cells/ml for both PBMC and HASMC. There were four conditions: (1) Control (no exposure); (2) Cyanide (exposure only); (3) B12a (cyanide exposure followed by B12a treatment); (4) NV118 (cyanide followed by NV118 treatment). In this study the key findings include: (1) Improvement in key mitochondrial respiratory states with the succinate prodrug (NV118) but not B12a; (2) Attenuation of superoxide production with treatment of NV118 but not with B12a treatment; (3) The changes in respiration were not secondary to increased mitochondrial content as measured by citrate synthase; (4) The use of easily accessible human blood cells showed similar mitochondrial response to both cyanide and treatment to HASMC. The use of a succinate prodrug to circumvent partial CIV inhibition by cyanide with clear reversal of cellular respiration and superoxide production that was not attributed to changes in mitochondrial content not seen by the use of B12a.</p>}},
  author       = {{Owiredu, Shawn and Ranganathan, Abhay and Greenwood, John C and Piel, Sarah and Janowska, Joanna I and Eckmann, David M and Kelly, Matthew and Ehinger, Johannes K and Kilbaugh, Todd J and Jang, David H}},
  issn         = {{2214-7500}},
  keywords     = {{Respiration; Cyanide; Mitochondria; Antidote}},
  language     = {{eng}},
  pages        = {{1263--1271}},
  publisher    = {{Elsevier}},
  series       = {{Toxicology Reports}},
  title        = {{In vitro comparison of hydroxocobalamin (B12a) and the mitochondrial directed therapy by a succinate prodrug in a cellular model of cyanide poisoning}},
  url          = {{http://dx.doi.org/10.1016/j.toxrep.2020.09.002}},
  doi          = {{10.1016/j.toxrep.2020.09.002}},
  volume       = {{7}},
  year         = {{2020}},
}