Perioperative Medicine  |   May 2018
Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein–induced Inflammation through a Vagomimetic Action in Mice
Author Notes
  • From the Department of Anesthesia and Perioperative Care and Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, California (J.H., X.F., D.L., Y.U., I.K.L., M.M.); the Department of Anesthesia, Tongling People’s Hospital, Tongling, People’s Republic of China (J.H.); and the Department of Anesthesia and Perioperative Medicine, University of California, Los Angeles, Los Angeles, California (S.V.).
  • Submitted for publication August 27, 2017. Accepted for publication November 21, 2017.
    Submitted for publication August 27, 2017. Accepted for publication November 21, 2017.×
  • Address correspondence to Dr. Maze: Zuckerberg San Francisco General, 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
Perioperative Medicine / Basic Science / Central and Peripheral Nervous Systems / Geriatric Anesthesia / Pharmacology
Perioperative Medicine   |   May 2018
Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein–induced Inflammation through a Vagomimetic Action in Mice
Anesthesiology 5 2018, Vol.128, 921-931. doi:10.1097/ALN.0000000000002038
Anesthesiology 5 2018, Vol.128, 921-931. doi:10.1097/ALN.0000000000002038
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.