Dexmedetomidine prevents cognitive decline by enhancing resolution of high mobility group box 1 protein-induced inflammation through a vagomimetic action in mice
Background: Inflammation initiated by damage-Associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine-induced reduction of damage-Associated molecular pattern-induced cognitive decline. Methods: Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage-Associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines. Results: Damage-Associated molecular pattern-induced cognitive decline and inflammation (mean ± SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 ± 8.69% vs. 41.45 ± 7.64%, P &lt; 0.0001; plasma interleukin [IL]-1β: 7.0 ± 2.2 pg/ml vs. 49.8 ± 6.0 pg/ml, P &lt; 0.0001; plasma IL-6: 3.2 ± 1.6 pg/ml vs. 19.5 ± 1.7 pg/ml, P &lt; 0.0001; hippocampal IL-1β: 4.1 ± 3.0 pg/mg vs. 41.6 ± 8.0 pg/mg, P &lt; 0.0001; hippocampal IL-6: 3.4 ± 1.3 pg/mg vs. 16.2 ± 2.7 pg/mg, P &lt; 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and α7 nicotinic acetylcholine receptors but not by α2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation-resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 ± 0.1 vs. 0.7 ± 0.1, P &lt; 0.0001; spleen: 1.5 ± 0.2 vs. 0.6 ± 0.2, P &lt; 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 ± 0.2 vs. 0.9 ± 0.2, P &lt; 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 ± 0.2 vs. 3.0 ± 0.3, P &lt; 0.0001) humoral mediators that was prevented by α7 nicotinic acetylcholine receptor blockade. Conclusions: Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-Associated molecular pattern-mediated cognitive decline. (Anesthesiology 2018; 128:921-31). © 2018, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.