Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein–induced Inflammation through a Vagomimetic Action in Mice. (May 2018)

• Record Type: Journal Article
• Authors: Hu, Jun; Vacas, Susana; Feng, Xiaomei; Lutrin, David; Uchida, Yosuke; Lai, Ieng Kit; Maze, Mervyn
• Is Part Of: Anesthesiology. Volume 128:Number 5(2018)
• Publication Date: 2018-05
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000002038
• Languages: English
• ISSNs: 0003-3022

Abstract

Abstract : 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 < 0.0001; plasma interleukin [IL]-1β: 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-1β: 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 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 < 0.0001; spleen: 1.5 ± 0.2 vs . 0.6 ± 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4 : 1.7 ± 0.2 vs . 0.9 ± 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4 : 1.0 ± 0.2 vs . 3.0 ± 0.3, P < 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. Abstract : In a preclinical model, dexmedetomidine prevented cognitive deficits resulting from administration of high molecular group box 1 protein via both vagomimetic and humoral pathways. The results are consistent with the notion that the cognitive deficits noted after surgery or medical illness may be prevented by the administration of dexmedetomidine.