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.

Keywords: 15d-PGJ(2); Anti-inflammation; Dexmedetomidine; PPARγ; α(2) adrenoceptors.