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

Journal of Inflammation

Research

Stephanie Myers¹  Daniel J. Buck¹  Randall L. Davis¹  J. Thomas Curtis¹  Kelly McCracken¹ 

[1] Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, 74107, Tulsa, OK, USA;

关键词: β-funaltrexamine;    Neuroinflammation;    Neuroprotective;    Chemokine;    Cytokine;    Nuclear factor-κB;    Opioid;    Peripheral inflammation;   

DOI  :  10.1186/s12950-023-00328-z

 received in 2022-09-15, accepted in 2023-01-15,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundInflammation 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.ResultsMale 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.ConclusionThese 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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