ArticleJournal of inflammation research2022
SK-Channel Activation Alters Peripheral Metabolic Pathways in Mice, but Not Lipopolysaccharide-Induced Fever or Inflammation.
Article in Journal of inflammation research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed, 3 citations in OpenAlex.
- Partial depletion of circulating neutrophil granulocytes in mice exacerbates the inflammatory response and hypothermia during LPS induced severe systemic inflammation.Frontiers in immunology · 2025Article
- Effects of Omega-3 Polyunsaturated Fatty Acids on the Formation of Adipokines, Cytokines, and Oxylipins in Retroperitoneal Adipose Tissue of Mice.International journal of molecular sciences · 2024Article
- Systemic Lipopolysaccharide Challenge Induces Inflammatory Changes in Rat Dorsal Root Ganglia: An Ex Vivo Study.International journal of molecular sciences · 2022Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposePreviously, we have shown that CyPPA (cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine), a pharmacological small-conductance calcium-activated potassium (SK)-channel positive modulator, antagonizes lipopolysaccharide (LPS)-induced cytokine expression in microglial cells. Here, we aimed to test its therapeutic potential for brain-controlled sickness symptoms, brain inflammatory response during LPS-induced systemic inflammation, and peripheral metabolic pathways in mice.
methodsMice were pretreated with CyPPA (15 mg/kg IP) 24 hours before and simultaneously with LPS stimulation (2.5 mg/kg IP), and the sickness response was recorded by a telemetric system for 24 hours. A second cohort of mice were euthanized 2 hours after CyPPA or solvent treatment to assess underlying CyPPA-induced mechanisms. Brain, blood, and liver samples were analyzed for inflammatory mediators or nucleotide concentrations using immunohistochemistry, real-time PCR and Western blot, or HPLC. Moreover, we investigated CyPPA-induced changes of UCP1 expression in brown adipose tissue (BAT)-explant cultures.
resultsCyPPA treatment did not affect LPS-induced fever, anorexia, adipsia, or expression profiles of inflammatory mediators in the hypothalamus or plasma or microglial reactivity to LPS (CD11b staining and CD68 mRNA expression). However, CyPPA alone induced a rise in core body temperature linked to heat production via altered metabolic pathways like reduced levels of adenosine, increased protein content, and increased UCP1 expression in BAT-explant cultures, but no alteration in ATP/ADP concentrations in the liver. CyPPA treatment was accompanied by altered pathways, including NFκB signaling, in the hypothalamus and cortex, while circulating cytokines remained unaltered.
conclusionOverall, while CyPPA has promise as a treatment strategy, in particular according to results from in vitro experiments, we did not reveal anti-inflammatory effects during severe LPS-induced systemic inflammation. Interestingly, we found that CyPPA alters metabolic pathways inducing short hyperthermia, most likely due to increased energy turnover in the liver and heat production in BAT.
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