Newly Published Free
Perioperative Medicine  |   June 2018
Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia
Author Notes
  • From the Departments of Physiology (D.-S.W., K.K., G.L., F.M., J.W., I.L., Y.-F.X., N.K.C., A.F.-E., A.J.R., B.A.O.), Anesthesia (A.S., B.A.O.), Pharmacology and Toxicology (A.J.R.), and Ophthalmology and Vision Science (J.M.S.) and the Leslie Dan Faculty of Pharmacy (Y.-F.X., R.P.B.), University of Toronto, Toronto, Ontario, Canada; the Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (S.A., B.A.O.); the Center for Neuroscience and Connectomics, Korea Institute of Science and Technology, Seoul, Korea (J.W., C.J.L.); and the Division of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (D.C., J.M.S.).
  • Submitted for publication December 19, 2017. Accepted for publication May 14, 2018.
    Submitted for publication December 19, 2017. Accepted for publication May 14, 2018.×
  • Research Support: Supported by foundation grant No. FDN-154312 from the Canadian Institutes of Health Research, Ottawa, Ontario, Canada (to Dr. Orser); by a Kirk Weber Award in Anesthesia from Sunnybrook Health Sciences Center, Toronto, Ontario, Canada (to Ms. Kaneshwaran); by funds from the Department of Anesthesia at the University of Toronto, Toronto, Ontario, Canada, and from the Canadian Anesthesia Research Foundation, Toronto, Ontario, Canada (to Dr. Avramescu); by Canadian Institutes of Health Research, Ottawa, Ontario, Canada, operating grant Nos. 119298 (to Dr. Ramsey) and 123448 (to Dr. Sivak); and by a Natural Sciences and Engineering Research Council, Ottawa, Ontario, Canada, Discovery grant No. RGPIN-2016-05538 and funds from the Canada Research Chair in Sensory Plasticity and Reconsolidation and the University of Toronto Center for the Study of Pain, Toronto, Ontario, Canada (to Dr. Bonin). The work was also supported by the Perioperative Brain Health Centre, Toronto, Ontario, Canada (http://www.perioperativebrainhealth.com).
    Research Support: Supported by foundation grant No. FDN-154312 from the Canadian Institutes of Health Research, Ottawa, Ontario, Canada (to Dr. Orser); by a Kirk Weber Award in Anesthesia from Sunnybrook Health Sciences Center, Toronto, Ontario, Canada (to Ms. Kaneshwaran); by funds from the Department of Anesthesia at the University of Toronto, Toronto, Ontario, Canada, and from the Canadian Anesthesia Research Foundation, Toronto, Ontario, Canada (to Dr. Avramescu); by Canadian Institutes of Health Research, Ottawa, Ontario, Canada, operating grant Nos. 119298 (to Dr. Ramsey) and 123448 (to Dr. Sivak); and by a Natural Sciences and Engineering Research Council, Ottawa, Ontario, Canada, Discovery grant No. RGPIN-2016-05538 and funds from the Canada Research Chair in Sensory Plasticity and Reconsolidation and the University of Toronto Center for the Study of Pain, Toronto, Ontario, Canada (to Dr. Bonin). The work was also supported by the Perioperative Brain Health Centre, Toronto, Ontario, Canada (http://www.perioperativebrainhealth.com).×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Orser: Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. beverley.orser@utoronto.ca. 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.
  • D.-S.W., K.K., and G.L. contributed equally to this article.
    D.-S.W., K.K., and G.L. contributed equally to this article.×
Article Information
Perioperative Medicine / Pharmacology
Perioperative Medicine   |   June 2018
Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia
Anesthesiology Newly Published on June 7, 2018. doi:10.1097/ALN.0000000000002311
Anesthesiology Newly Published on June 7, 2018. doi:10.1097/ALN.0000000000002311
Abstract

Background: Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of α5 subunit-containing γ-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an α2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of α5 γ-aminobutyric acid type A receptors.

Methods: Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. γ-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied.

Results: The etomidate-induced sustained increase in α5 γ-aminobutyric acid type A receptor cell-surface expression was reduced by dexmedetomidine (mean ± SD, etomidate: 146.4 ± 51.6% vs. etomidate + dexmedetomidine: 118.4 ± 39.1% of control, n = 8 each). Dexmedetomidine also reduced the persistent increase in tonic inhibitory current in hippocampal neurons (etomidate: 1.44 ± 0.33 pA/pF, n = 10; etomidate + dexmedetomidine: 1.01 ± 0.45 pA/pF, n = 9). Similarly, dexmedetomidine prevented a sevoflurane-induced increase in the tonic current. Dexmedetomidine stimulated astrocytes to release brain-derived neurotrophic factor, which acted as a paracrine factor to reduce excessive α5 γ-aminobutyric acid type A receptor function in neurons. Finally, dexmedetomidine attenuated memory and problem-solving deficits after anesthesia.

Conclusions: Dexmedetomidine prevented excessive α5 γ-aminobutyric acid type A receptor function after anesthesia. This novel α2 adrenergic receptor- and brain-derived neurotrophic factor-dependent pathway may be targeted to prevent delirium.