Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia.

Authors:
Dian-Shi Wang
Dian-Shi Wang
Fourth Military Medical University
China
Gang Lei
Gang Lei
Institute of Genetics and Developmental Biology
China
Fariya Mostafa
Fariya Mostafa
University of Toronto
Junhui Wang
Junhui Wang
Zhejiang University
China
Irene Lecker
Irene Lecker
Mount Sinai Hospital
Canada
Sinziana Avramescu
Sinziana Avramescu
University of Toronto
Canada
Yu-feng Xie
Yu-feng Xie
Soochow University
China

Anesthesiology 2018 Sep;129(3):477-489

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.) Ophthalmology and Vision Science (J.M.S.) 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.) the Division of Vision Sciences, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (D.C., J.M.S.).

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: 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.

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Dexmedetomidine Prevents Excessive ?-Aminobutyric Acid Type A Receptor Function after Anesthesia


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September 2018
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