Newly Published
Critical Care Medicine  |   May 2020
Dexmedetomidine Exerts an Anti-inflammatory Effect via α2 Adrenoceptors to Prevent Lipopolysaccharide-induced Cognitive Decline in Mice
Author Notes
  • From the Department of Anesthesiology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China (R.L., P.Z.); the Center for Brain Science, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China (R.L.); and the Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care (R.L., I.K.L., J.Z.P., M.M.) and the Brain and Spinal Injury Center (J.Z.P.), University of California, San Francisco, California.
  • Part of the work presented in this article has been presented at the Association of University Anesthesiologists Annual Meeting in Montreal, Canada, May 17, 2019; the International Anesthesia Research Society Annual Meeting in Montreal, Canada, May 18, 2019; and the Kosaka Best Abstract Symposium in Montreal, Canada, May 19, 2019.
    Part of the work presented in this article has been presented at the Association of University Anesthesiologists Annual Meeting in Montreal, Canada, May 17, 2019; the International Anesthesia Research Society Annual Meeting in Montreal, Canada, May 18, 2019; and the Kosaka Best Abstract Symposium in Montreal, Canada, May 19, 2019.×
  • Submitted for publication July 19, 2019. Accepted for publication April 28, 2020.
    Submitted for publication July 19, 2019. Accepted for publication April 28, 2020.×
  • Correspondence: Address correspondence to Dr. Maze: Center for Cerebrovascular Research, Zuckerberg San Francisco General Hospital, 1001 Potrero Avenue, Building 10, Room 1206, San Francisco, California 94110-3518. mervyn.maze@ucsf.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Geriatric Anesthesia / Pharmacology
Critical Care Medicine   |   May 2020
Dexmedetomidine Exerts an Anti-inflammatory Effect via α2 Adrenoceptors to Prevent Lipopolysaccharide-induced Cognitive Decline in Mice
Anesthesiology Newly Published on May 28, 2020. doi:https://doi.org/10.1097/ALN.0000000000003390
Anesthesiology Newly Published on May 28, 2020. doi:https://doi.org/10.1097/ALN.0000000000003390
Abstract

Background: Clinical studies have shown that dexmedetomidine ameliorates cognitive decline in both the postoperative and critical care settings. This study determined the mechanism(s) for the benefit provided by dexmedetomidine in a medical illness in mice induced by lipopolysaccharide.

Methods: Cognitive decline, peripheral and hippocampal inflammation, blood–brain barrier permeability, and inflammation resolution were assessed in male mice. Dexmedetomidine was administered in the presence of lipopolysaccharide and in combination with blockers. Cultured macrophages (RAW 264.7; BV-2) were exposed to lipopolysaccharide ± dexmedetomidine ± yohimbine; tumor necrosis factor α release into the medium and monocyte NFκB activity was determined.

Results: In vivo, lipopolysaccharide-induced cognitive decline and inflammation (mean ± SD) were reversed by dexmedetomidine (freezing time, 55.68 ± 12.31 vs. 35.40 ± 17.66%, P = 0.0286, n = 14; plasma interleukin [IL]-1β: 30.53 ± 9.53 vs. 75.68 ± 11.04 pg/ml, P < 0.0001; hippocampal IL-1β: 3.66 ± 1.88 vs. 28.73 ± 5.20 pg/mg, P < 0.0001; n = 8), which was prevented by α2 adrenoceptor antagonists. Similar results were found in 12-month-old mice. Lipopolysaccharide also increased blood–brain barrier leakage, inflammation-resolution orchestrator, and proresolving and proinflammatory mediators; each lipopolysaccharide effect was attenuated by dexmedetomidine, and yohimbine prevented dexmedetomidine’s attenuating effect. In vitro, lipopolysaccharide-induced tumor necrosis factor α release (RAW 264.7: 6,308.00 ± 213.60 vs. 7,767.00 ± 358.10 pg/ml, P < 0.0001; BV-2: 1,075.00 ± 40.41 vs. 1,280.00 ± 100.30 pg/ml, P = 0.0003) and NFκB–p65 activity (nuclear translocation [RAW 264.7: 1.23 ± 0.31 vs. 2.36 ± 0.23, P = 0.0031; BV-2: 1.08 ± 0.26 vs. 1.78 ± 0.14, P = 0.0116]; phosphorylation [RAW 264.7: 1.22 ± 0.40 vs. 1.94 ± 0.23, P = 0.0493; BV-2: 1.04 ± 0.36 vs. 2.04 ± 0.17, P = 0.0025]) were reversed by dexmedetomidine, which was prevented by yohimbine.

Conclusions: Preclinical studies suggest that the cognitive benefit provided by dexmedetomidine in mice administered lipopolysaccharide is mediated through α2 adrenoceptor–mediated anti-inflammatory pathways.

Editor’s Perspective:

What We Already Know about This Topic:

  • Administration of lipopolysaccharide to young and middle-aged mice is associated with neuroinflammation and cognitive impairment

  • Dexmedetomidine has been shown to decrease neuroinflammation in mice

What This Article Tells Us That Is New:

  • Administration of dexmedetomidine to mice treated with lipopolysaccharide decreased neuroinflammation and cognitive impairment in both young and aged mice

  • The effects of dexmedetomidine on neuroinflammation and cognitive impairment in mice treated with lipopolysaccharide are likely mediated by α2 adrenoceptor–mediated anti-inflammatory pathways