Newly Published
Perioperative Medicine  |   December 2017
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.×
  • Acknowledgments: The authors wish to thank Jinbao Chen, M.D. (Department of Anesthesia, Tongling People’s Hospital, Tongling Anhui, People’s Republic of China), for providing postdoctoral support to Dr. Hu and to Christopher Chang, B.A. (University of California, Santa Cruz, California), for help with the preparation of the manuscript.
    Acknowledgments: The authors wish to thank Jinbao Chen, M.D. (Department of Anesthesia, Tongling People’s Hospital, Tongling Anhui, People’s Republic of China), for providing postdoctoral support to Dr. Hu and to Christopher Chang, B.A. (University of California, Santa Cruz, California), for help with the preparation of the manuscript.×
  • Research Support: Supported by grant No. R01GM104194 from the National Institutes of Health, Bethesda, Maryland (to Dr. Maze).
    Research Support: Supported by grant No. R01GM104194 from the National Institutes of Health, Bethesda, Maryland (to Dr. Maze).×
  • Competing Interests: Dr. Maze is a coinventor on a patent for the use of dexmedetomidine for sedation. Between 1987 and 1991, Dr. Maze’s laboratory at Stanford University (Stanford, California) received $250,000 for the assignment of the patent to Farmos (Espoo, Finland), the company that synthesized dexmedetomidine. Between 1995 and 2008, Dr. Maze was intermittently paid as a consultant by Orion-Farmos (Espoo, Finland), Abbott Labs (Chicago, Illinois), and Hospira (Lake Forest, Illinois) for advising on the pivotal phase III clinical trials, approval of the new drug application, and subsequent marketing of the product. Dr. Maze has not received any payments for at least the last 5 yr. Dr. Maze has not and will not receive royalty payments for sales of dexmedetomidine. The other authors declare no competing interests.
    Competing Interests: Dr. Maze is a coinventor on a patent for the use of dexmedetomidine for sedation. Between 1987 and 1991, Dr. Maze’s laboratory at Stanford University (Stanford, California) received $250,000 for the assignment of the patent to Farmos (Espoo, Finland), the company that synthesized dexmedetomidine. Between 1995 and 2008, Dr. Maze was intermittently paid as a consultant by Orion-Farmos (Espoo, Finland), Abbott Labs (Chicago, Illinois), and Hospira (Lake Forest, Illinois) for advising on the pivotal phase III clinical trials, approval of the new drug application, and subsequent marketing of the product. Dr. Maze has not received any payments for at least the last 5 yr. Dr. Maze has not and will not receive royalty payments for sales of dexmedetomidine. The other authors declare no competing interests.×
  • Correspondence: Address correespondence 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 / Geriatric Anesthesia / Pharmacology
Perioperative Medicine   |   December 2017
Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein–induced Inflammation through a Vagomimetic Action in Mice
Anesthesiology Newly Published on December 21, 2017. doi:10.1097/ALN.0000000000002038
Anesthesiology Newly Published on December 21, 2017. 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.