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Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation

BACKGROUND: Inflammation is present in neurological and peripheral disorders. Thus, targeting inflammation has emerged as a viable option for treating these disorders. Previous work indicated pretreatment with beta-funaltrexamine (β-FNA), a selective mu-opioid receptor (MOR) antagonist, inhibited in...

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Autores principales: Myers, Stephanie, McCracken, Kelly, Buck, Daniel J., Curtis, J. Thomas, Davis, Randall L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9878921/
https://www.ncbi.nlm.nih.gov/pubmed/36698151
http://dx.doi.org/10.1186/s12950-023-00328-z
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author Myers, Stephanie
McCracken, Kelly
Buck, Daniel J.
Curtis, J. Thomas
Davis, Randall L.
author_facet Myers, Stephanie
McCracken, Kelly
Buck, Daniel J.
Curtis, J. Thomas
Davis, Randall L.
author_sort Myers, Stephanie
collection PubMed
description BACKGROUND: Inflammation is present in neurological and peripheral disorders. Thus, targeting inflammation has emerged as a viable option for treating these disorders. Previous work indicated pretreatment with beta-funaltrexamine (β-FNA), a selective mu-opioid receptor (MOR) antagonist, inhibited inflammatory signaling in vitro in human astroglial cells, as well as lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like-behavior in mice. This study explores the protective effects of β-FNA when treatment occurs 10 h after LPS administration and is the first-ever investigation of the sex-dependent effects of β-FNA on LPS-induced inflammation in the brain and peripheral tissues, including the intestines. RESULTS: Male and female C57BL/6J mice were administered LPS followed by treatment with β-FNA-immediately or 10 h post-LPS. Sickness- and anxiety-like behavior were assessed using an open-field test and an elevated-plus-maze test, followed by the collection of whole brain, hippocampus, prefrontal cortex, cerebellum/brain stem, plasma, spleen, liver, large intestine (colon), proximal small intestine, and distal small intestine. Levels of inflammatory chemokines/cytokines (interferon γ-induced-protein, IP-10 (CXCL10); monocyte-chemotactic-protein 1, MCP-1 (CCL2); interleukin-6, IL-6; interleukin-1β, IL-1β; and tumor necrosis factor-alpha, TNF-α) in tissues were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to assess nuclear factor-kappa B (NF-κB) expression. There were sex-dependent differences in LPS-induced inflammation across brain regions and peripheral tissues. Overall, LPS-induced CXCL10, CCL2, TNF-α, and NF-κB were most effectively downregulated by β-FNA; and β-FNA effects differed across brain regions, peripheral tissues, timing of the dose, and in some instances, in a sex-dependent manner. β-FNA reduced LPS-induced anxiety-like behavior most effectively in female mice. CONCLUSION: These findings provide novel insights into the sex-dependent anti-inflammatory effects of β-FNA and advance this agent as a potential therapeutic option for reducing both neuroinflammation an intestinal inflammation.
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spelling pubmed-98789212023-01-27 Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation Myers, Stephanie McCracken, Kelly Buck, Daniel J. Curtis, J. Thomas Davis, Randall L. J Inflamm (Lond) Research BACKGROUND: Inflammation is present in neurological and peripheral disorders. Thus, targeting inflammation has emerged as a viable option for treating these disorders. Previous work indicated pretreatment with beta-funaltrexamine (β-FNA), a selective mu-opioid receptor (MOR) antagonist, inhibited inflammatory signaling in vitro in human astroglial cells, as well as lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like-behavior in mice. This study explores the protective effects of β-FNA when treatment occurs 10 h after LPS administration and is the first-ever investigation of the sex-dependent effects of β-FNA on LPS-induced inflammation in the brain and peripheral tissues, including the intestines. RESULTS: Male and female C57BL/6J mice were administered LPS followed by treatment with β-FNA-immediately or 10 h post-LPS. Sickness- and anxiety-like behavior were assessed using an open-field test and an elevated-plus-maze test, followed by the collection of whole brain, hippocampus, prefrontal cortex, cerebellum/brain stem, plasma, spleen, liver, large intestine (colon), proximal small intestine, and distal small intestine. Levels of inflammatory chemokines/cytokines (interferon γ-induced-protein, IP-10 (CXCL10); monocyte-chemotactic-protein 1, MCP-1 (CCL2); interleukin-6, IL-6; interleukin-1β, IL-1β; and tumor necrosis factor-alpha, TNF-α) in tissues were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to assess nuclear factor-kappa B (NF-κB) expression. There were sex-dependent differences in LPS-induced inflammation across brain regions and peripheral tissues. Overall, LPS-induced CXCL10, CCL2, TNF-α, and NF-κB were most effectively downregulated by β-FNA; and β-FNA effects differed across brain regions, peripheral tissues, timing of the dose, and in some instances, in a sex-dependent manner. β-FNA reduced LPS-induced anxiety-like behavior most effectively in female mice. CONCLUSION: These findings provide novel insights into the sex-dependent anti-inflammatory effects of β-FNA and advance this agent as a potential therapeutic option for reducing both neuroinflammation an intestinal inflammation. BioMed Central 2023-01-25 /pmc/articles/PMC9878921/ /pubmed/36698151 http://dx.doi.org/10.1186/s12950-023-00328-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Myers, Stephanie
McCracken, Kelly
Buck, Daniel J.
Curtis, J. Thomas
Davis, Randall L.
Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation
title Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation
title_full Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation
title_fullStr Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation
title_full_unstemmed Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation
title_short Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation
title_sort anti-inflammatory effects of β-fna are sex-dependent in a pre-clinical model of lps-induced inflammation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9878921/
https://www.ncbi.nlm.nih.gov/pubmed/36698151
http://dx.doi.org/10.1186/s12950-023-00328-z
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