Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 May;128(5):921-931.
doi: 10.1097/ALN.0000000000002038.

Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein-induced Inflammation through a Vagomimetic Action in Mice

Jun Hu  1 , Susana Vacas, Xiaomei Feng, David Lutrin, Yosuke Uchida, Ieng Kit Lai, Mervyn Maze
Affiliations

Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein-induced Inflammation through a Vagomimetic Action in Mice

Jun Hu et al. Anesthesiology. 2018 May.

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.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest

MM is a co-inventor on a patent for the use of dexmedetomidine for sedation. Between 1987–1991 MM’s laboratory at Stanford University received $250,000 for the assignment of the patent to Farmos, the company that synthesized dexmedetomidine. Between 1995–2008, MM was intermittently paid as a consultant by Orion-Farmos, Abbott Labs and Hospira for advising on the pivotal Phase III clinical trials, approval of the New Drug Application, and for subsequent marketing of the product. MM has not received any payments for at least the last 5 years. MM has not and will not receive royalty payments for sales of dexmedetomidine.

Figures

Figure 1:
Figure 1:. Study design.
(A) Mice were randomly allocated to 10 groups (n=15/group) and were pre-treated intraperitoneally (ip) with antagonists (yohimbine/atipamezole/methyllycaconitine). Thirty minutes later mice were trained in the trace-fear conditioning paradigm. After the training session, high mobility group box 1 protein (HMGB1) or vehicle (phosphate-buffered saline) was administered ip dexmedetomidine was administered every 2 hours × 3 times. 72 hours after HMGB1, testing was performed in the trace-fear conditioning. (B) Mice were randomly allocated to 10 groups (n=8/group) and were pre-treated ip with antagonists (yohimbine/atipamezole/methyllycaconitine) and 30 minutes later HMGB1 was administered. Dexmedetomidine was administered every 2 hours × 3 times. Blood and tissue were collected 24 hours later. (C) Mice were randomly allocated to three groups (n=15/group): control (vehicle only); surgery/anesthesia and surgery/anesthesia + dexmedetomidine. Mice were trained in the trace fear-conditioning paradigm. After the training session, animals were anesthetized with isoflurane and subjected to aseptic trauma. Dexmedetomidine was administered and the mice were tested in the trace-fear conditioning 3 days later. (D) Mice were randomly allocated to 3 groups (n=5–6/group): control (vehicle only); surgery/anesthesia and surgery/anesthesia + dexmedetomidine. Mice were anesthetized with isoflurane and subjected to aseptic trauma. Dexmedetomidine was administered and blood and tissue were collected 24 hours later.
Figure 2.
Figure 2.. Dexmedetomidine prevents HMGB1-induced decrement in freezing behavior in an Atipamezole and Methyllycaconitine sensitive manner.
Ten groups of randomly-assigned mice (n=15/group) were administered antagonists (methyllycaconitine, atipamezole, yohimbine) prior to HMGB1 and subjected to trace-fear conditioning training with and without dexmedetomidine exposure. Testing for freezing behavior in the trace-fear conditioning context was undertaken 72 hours later. Freezing time data are expressed as means ± SD and were analyzed by one-way ANOVA and Tukey post hoc test, * = P<0.0001 for comparisons shown.
Figure 3:
Figure 3:. Dexmedetomidine prevents HMGB1-induced peripheral inflammation in an Atipamezole and Methyllycaconitine sensitive manner
Ten groups of randomly-assigned mice (n=8/group) were administered antagonists (methyllycaconitine, atipamezole, yohimbine) prior to HMGB1 in the presence or absence of dexmedetomidine. Twenty-four hours after HMGB1, mice were sacrificed and the blood was harvested and assayed by ELISA for circulating IL-1β (A) and IL-6 (B). Data are expressed as means ± SD and analyzed by one-way ANOVA and Tukey post hoc test. * = P<0.0001, # = P<0.01 for comparisons shown.
Figure 4:
Figure 4:. Dexmedetomidine prevents HMGB1-induced hippocampal inflammation in an Atipamezole and Methyllycaconitine sensitive manner
Ten groups of randomly-assigned mice (n=8/group) were administered antagonists (methyllycaconitine, atipamezole, yohimbine) prior to HMGB1 in the presence or absence of dexmedetomidine. Twenty-four hours after HMGB1, mice were sacrificed and the hippocampus was harvested and assayed by ELISA for IL-1β (A) and IL-6 (B). Data are expressed as means ± SD and were analyzed by one-way ANOVA and Tukey post hoc test, * = P<0.0001 for comparisons shown.
Figure 5.
Figure 5.. Dexmedetomidine prevents HMGB1-induced downregulation of Netrin-1 expression in the lung (A) and spleen (B) in an α7nicotinic acetylcholine receptor dependent manner.
Four groups of randomly-assigned mice (n=5/group) were administered saline vehicle (control), HMGB1 alone, HMGB1+ dexmedetomidine, or HMGB1 + dexmedetomidine + methyllycaconitine. Twenty-four hours later, mice were sacrificed and lung (A) and spleen (B) were harvested for expression of netrin-1 by immunoblotting. Data are expressed as means ± SD fold-change relative to control and were analyzed by one-way ANOVA and Tukey post hoc test. # = P<0.05 and * = P<0.0001 for comparisons shown
Figure 6.
Figure 6.. Dexmedetomidine downregulates the circulating pro-inflammatory mediator leukotriene B4, (LTB4; A) and upregulates the circulating pro-resolving mediator lipoxin A4 (LXA4; B)
Four groups of randomly-assigned mice (n=8/group) were administered saline vehicle (control), HMGB1 alone, HMGB1+ dexmedetomidine, or HMGB1 + dexmedetomidine + methyllycaconitine. Twenty-four hours later, mice were sacrificed and the blood was harvested and assayed by ELISA for plasma LTB4 (A) and LXA4 (B). Data are expressed as means ± SD fold-change relative to control and were analyzed by one-way ANOVA and Tukey post hoc test. * = P<0.0001 for comparisons shown.
Figure 7
Figure 7. Dexmedetomidine reverses HMGB1-induced leakage of blood brain barrier
Three groups of randomly-assigned mice (n=5/group) were treated with vehicle (control), HMGB1, or HMGB1 + dexmedetomidine. 24 hours after treatment, mice were sacrificed and the brains were harvested for immunoblotting of albumin expression. Data are expressed as means ± SD relative to control and were analyzed by one-way ANOVA and Tukey post hoc test. * = P<0.01 for comparisons shown.
Figure 8
Figure 8. Dexmedetomidine reverses Surgery-induced Cognitive Decline (A) and Peripheral (B), and Neuro-Inflammation (C)
Three groups of randomly-assigned mice (n=15/group) were treated with (i) vehicle, (ii) tibia fracture under anesthesia (Sx/Anesth) + vehicle and (iii) Sx/Anesth + dexmedetomidine prior to training in the trace fear-conditioning paradigm (A). Testing for freezing behavior in the trace-fear conditioning context was undertaken 72 hours later. Freezing time data are expressed as means ± SD and were analyzed by one-way ANOVA and Tukey post hoc test. Three groups of randomly-assigned mice (n=6/group) were treated with (i) vehicle, (ii) tibia fracture under anesthesia (Sx/Anesth) + vehicle and (iii) Sx/Anesth + dexmedetomidine and mice were sacrificed at 24 hours and blood and brain were harvested. Plasma IL-6 was assayed by ELISA (B) and hippocampal IL-6 was assayed by quantitative PCR (C). The means ± SD of the mean for expression of IL-6 protein (B) and mRNA (C) and were analyzed by one-way ANOVA and Tukey post hoc test. # = P < 0.05; * = P < 0.01; **P<0.0001
See this image and copyright information in PMC

References

    1. Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M: Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A 2010; 107: 20518–22 - PMC - PubMed
    1. Terrando N, Eriksson LI, Ryu JK, Yang T, Monaco C, Feldmann M, Jonsson Fagerlund M, Charo IF, Akassoglou K, Maze M: Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol 2011; 70: 986–95 - PMC - PubMed
    1. Feng X, Valdearcos M, Uchida Y, Lutrin D, Koliwad SK, Maze M: Microglia mediate postoperative hippocampal neuroinflammation and cognitive decline in mice. JCI Insight 2017; 2: e91229. - PMC - PubMed
    1. Forsberg A, Cervenka S, Fagerlun MJ, Rasmussen L, Zetterberg H, Harris HE, Stridh P, Christensson E, Granstrom A, Schening A, Dymmel K, Knave N, Terrando N, Maze M, Borg J, A. V, Varrone A, Halldin C, Blennow K, Farde L, Eriksson L: The immune response of the human brain to abdominal surgery. Ann Neurol 2017; 84: 572–82 - PubMed
    1. Vacas S, Degos V, Tracey KJ, Maze M: High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages. Anesthesiology 2014; 120: 1160–7 - PMC - PubMed

Publication types