Anti-inflammatory effects of a p38 MAP kinase inhibitor, doramapimod, against bacterial cell wall toxins in equine whole blood.
Abstract: Doramapimod (BIRB-796-BS), is an anti-inflammatory compound, acting through p38 MAPK inhibition, but its anti-inflammatory effects have not previously been studied in the horse. Whole blood aliquots from healthy horses diluted 1:1 with cell culture medium were incubated for 21 h with 1 μg/ml of lipopolysaccharide (LPS), lipoteichoic acid (LTA) or peptidoglycan (PGN) in the presence of increasing concentrations of doramapimod (3 × 10 M to 10 M). Cell bioassays were used to measure TNF-α and IL-1β activity. Doramapimod significantly and potently inhibited TNF-α and IL-1β activity induced by all three bacterial toxins. There was no significant difference in IC or maximum inhibition of TNF-α or IL-1β production between any of the toxins. Maximum inhibition of IL-1β was higher than that of TNF-α for all toxins, and this difference was significant for LPS (P = 0.04). Doramapimod was a potent inhibitor of TNF-α and IL-1β for inflammation induced by LPS, LTA and PGN, with potency much greater than that of other drugs previously tested using similar methods.
Copyright © 2019 Elsevier B.V. All rights reserved.
Publication Date: 2019-12-17 PubMed ID: 31877483DOI: 10.1016/j.vetimm.2019.109994Google Scholar: Lookup
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Summary
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The researchers in this study explored the anti-inflammatory effects of a compound called doramapimod in horses, discovering that it significantly inhibited inflammation induced by certain bacterial toxins.
Research Background
- The study focuses on the anti-inflammatory compound doramapimod (BIRB-796-BS), which works by inhibiting p38 MAPK, a protein involved in the signaling processes of cells, particularly in responses to stress such as inflammation.
- Prior to this research, the anti-inflammatory effects of doramapimod had not been studied in equine models.
Methodology
- The researchers used blood samples from healthy horses, diluted these samples with cell culture medium, and then incubated them with three different bacterial toxins: lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN).
- The blood samples were also treated with different concentrations of doramapimod to observe its effect on the activity of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), two important markers of inflammation.
Results
- The results showed that doramapimod significantly inhibited both TNF-α and IL-1β activity induced by all three bacterial toxins, indicating that it has a potent anti-inflammatory effect.
- The compound inhibited IL-1β more effectively than TNF-α, particularly in inflammatory response induced by LPS. Nevertheless, there was no significant difference in the amount of doramapimod required to inhibit half-maximum (IC) or maximum production of TNF-α or IL-1β induced by any of the toxins.
Conclusion
- This study showed that doramapimod is a potent inhibitor of inflammation induced by LPS, LTA, and PGN in equine blood.
- Researchers noted that doramapimod’s potency was greater than that of other drugs previously tested using similar methodologies. These results open up potential avenues for using doramapimod in treating inflammatory conditions in horses.
Cite This Article
APA
Bauquier JR, Tennent-Brown BS, Tudor E, Bailey SR.
(2019).
Anti-inflammatory effects of a p38 MAP kinase inhibitor, doramapimod, against bacterial cell wall toxins in equine whole blood.
Vet Immunol Immunopathol, 220, 109994.
https://doi.org/10.1016/j.vetimm.2019.109994 Publication
Researcher Affiliations
- Department of Veterinary Clinical Sciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Australia. Electronic address: jbauquier@unimelb.edu.au.
- Department of Veterinary Clinical Sciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Australia.
- Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Australia.
- Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Australia.
MeSH Terms
- Animals
- Anti-Inflammatory Agents / pharmacology
- Bacterial Toxins / antagonists & inhibitors
- Biological Assay
- Cell Line
- Horses
- Interleukin-1beta / blood
- Lipopolysaccharides / pharmacology
- Mice
- Naphthalenes / pharmacology
- Peptidoglycan / pharmacology
- Pyrazoles / pharmacology
- Signal Transduction / drug effects
- Teichoic Acids / pharmacology
- Tumor Necrosis Factor-alpha / blood
- p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Conflict of Interest Statement
Declaration of Competing Interest This compound is the subject of a patent application filed by the University of Melbourne (Patent number PCT/AU2018/050120, filed 15 Feb 2018).
Citations
This article has been cited 1 times.- Bauquier J, Tudor E, Bailey S. Effect of the p38 MAPK inhibitor doramapimod on the systemic inflammatory response to intravenous lipopolysaccharide in horses.. J Vet Intern Med 2020 Sep;34(5):2109-2116.
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