Dexmedetomidine inhibits LPS-induced inflammatory responses through peroxisome proliferator-activated receptor gamma (PPARγ) activation following binding to α2 adrenoceptors.

Abstract

Over the past decade, dexmedetomidine (DEX) has been found to possess an anti-inflammatory effect. However, the local anti-inflammatory mechanism of DEX has not been fully clarified. Some intracellular inflammatory pathways lead to negative feedback during the inflammatory process. The cyclooxygenase (COX) cascade synthesizes prostaglandins (PGs) and plays a key role in inflammation, but is known to also have anti-inflammatory properties through an alternative route of a PGD2 metabolite, 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), and its receptor, peroxisome proliferator-activated receptor gamma (PPARγ). Therefore, we hypothesized that DEX inhibits LPS-induced inflammatory responses through 15d-PGJ2 and/or PPARγ activation, and evaluated the effects of DEX on these responses. The RAW264.7 mouse macrophage-like cells were pre-incubated with DEX, followed by the addition of LPS to induce inflammatory responses. Concentrations of TNFα, IL-6, PGE2, and 15d-PGJ2 in the supernatants of the cells were measured, and gene expressions of PPARγ and COX-2 were evaluated in the cells. Furthermore, we evaluated whether a selective α2 adrenoceptor antagonist, yohimbine or a selective PPARγ antagonist, T0070907, reversed the effects of DEX on the LPS-induced inflammatory responses. DEX inhibited LPS-induced TNFα, IL-6, and PGE2 productions and COX-2 mRNA expression, and the effects of DEX were reversed by yohimbine. On the other hand, DEX significantly increased 15d-PGJ2 production and PPARγ mRNA expression, and yohimbine reversed these DEX's effects. Furthermore, T0070907 reversed the anti-inflammatory effects of DEX on TNFα and IL-6 productions in the cells. These results suggest that DEX inhibits LPS-induced inflammatory responses through PPARγ activation following binding to α2 adrenoceptors.

• Authors: Maki Fujimoto, Hitoshi Higuchi, Yuka Honda-Wakasugi, Saki Miyake, Yukiko Nishioka, Akiko Yabuki-Kawase, Shigeru Maeda, Takuya Miyawaki
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 892 Pg. 173733 (Feb 05 2021) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 33220278 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• 15-deoxyprostaglandin J2
• ADRB2 protein, mouse
• Adrenergic alpha-2 Receptor Agonists
• Anti-Inflammatory Agents
• Interleukin-6
• Lipopolysaccharides
• PPAR gamma
• Pparg protein, mouse
• Receptors, Adrenergic, beta-2
• Tnf protein, mouse
• Tumor Necrosis Factor-alpha
• interleukin-6, mouse
• lipopolysaccharide, E coli O55-B5
• Dexmedetomidine
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Dinoprostone
• Prostaglandin D2

Topics

• Adrenergic alpha-2 Receptor Agonists (metabolism, pharmacology)
• Animals
• Anti-Inflammatory Agents (metabolism, pharmacology)
• Cyclooxygenase 2 (genetics, metabolism)
• Dexmedetomidine (metabolism, pharmacology)
• Dinoprostone (metabolism)
• Inflammation (chemically induced, metabolism, prevention & control)
• Interleukin-6 (metabolism)
• Lipopolysaccharides (toxicity)
• Macrophages (drug effects, metabolism, pathology)
• Mice
• PPAR gamma (agonists, genetics, metabolism)
• Prostaglandin D2 (analogs & derivatives, metabolism)
• Protein Binding
• RAW 264.7 Cells
• Receptors, Adrenergic, beta-2 (drug effects, metabolism)
• Signal Transduction
• Tumor Necrosis Factor-alpha (metabolism)