UCSF

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.