Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia. (September 2018)

• Record Type: Journal Article
• Authors: Wang, Dian-Shi; Kaneshwaran, Kirusanthy; Lei, Gang; Mostafa, Fariya; Wang, Junhui; Lecker, Irene; Avramescu, Sinziana; Xie, Yu-Feng; Chan, Nathan K.; Fernandez-Escobar, Alejandro; Woo, Junsung; Chan, Darren; Ramsey, Amy J.; Sivak, Jeremy M.; Lee, C. Justin; Bonin, Robert P.; Orser, Beverley A.
• Is Part Of: Anesthesiology. Volume 129:Number 3(2018)
• Publication Date: 2018-09
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000002311
• Languages: English
• ISSNs: 0003-3022

Abstract

Abstract : What We Already Know about This Topic: Dexmedetomidine is effective in reducing delirium in the postoperative period and in the intensive care unit in patients and prevents memory deficits in experimental animals subjected to anesthesia. The mechanism by which dexmedetomidine preserves cognition is not clear. In experimental models, even a single anesthetic exposure leads to a sustained increase in the expression of cell-surface γ-aminobutyric acid type A receptors that contain α5 subunits. Whether dexmedetomidine reduces this increase and preserves cognition was evaluated. What This Article Tells Us That Is New: Dexmedetomidine, by an α2 receptor-mediated release of brain-derived neurotrophic factor from astrocytes, reduced neuronal α5 γ-aminobutyric acid type A receptor expression and prevented cognitive deficits after anesthesia. The data suggest that suppression of anesthesia-induced sustained increase in α5 γ-aminobutyric acid type A receptor expression may be a potential therapeutic target for the prevention of postoperative and intensive care unit delirium. 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. Abstract : Dexmedetomidine, by an α2 receptor-mediated release of brain-derived neurotrophic factor from astrocytes, reduced neuronal α5 γ-aminobutyric acid type A receptor expression and prevented cognitive deficits after anesthesia. The data suggest that suppression of anesthesia-induced sustained increase in α5 γ-aminobutyric acid type A receptor expression may be a potential therapeutic target for the prevention of postoperative and intensive care unit delirium.