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 dexmedeto-midine-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 < 0.0001; plasma interleukin [IL]-1 beta: 7.0 +/- 2.2 pg/ml vs. 49.8 +/- 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 +/- 1.6 pg/ml vs. 19.5 +/- 1.7 pg/ml, P < 0.0001; hippocampal IL-1 beta: 4.1 +/- 3.0 pg/mg vs. 41.6 +/- 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 +/- 1.3 pg/mg vs. 16.2 +/- 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and alpha(7) nicotinic acetylcholine receptors but not by alpha(2) 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 < 0.0001; spleen: 1.5 +/- 0.2 vs. 0.6 +/- 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A(4) : 1.7 +/- 0.2 vs. 0.9 +/- 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B-4 : 1.0 +/- 0.2 vs. 3.0 +/- 0.3, P < 0.0001) humoral mediators that was prevented by alpha(7) nicotinic acetylcholine receptor blockade. Conclusions: Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern-mediated cognitive decline.