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

Abstract

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.

Prevalence of postoperative delirium according to the intraoperative general anesthetic agents in patients undergoing cardiac surgery: A retrospective and propensity-score matched study

“…Dexmedetomidine has been known to have neuroprotective effects (Wang et al, 2018). However, the exact mechanism through which dexmedetomidine reduces the incidence factors were found in the present study, which included older age, emergency surgery, and preoperative lower albumin levels.…”

Perioperative Neurocognitive Disorder

“…A vast array of different cell types have been studied in the quest to understand the basis of anesthetic-induced perioperative neurocognitive disorder. 10,[28][29][30][31][32][33][34][35][36][37][38][39][40] Stable cell lines (e.g., Chinese hamster ovary, human embryonic kidney, neuroglioma), isolated primary cells (e.g., hippocampal neurons grown in dissociated cell cultures), stem cells (e.g., neural or mesenchymal progenitor cells, and human-induced pluripotent stem cells and derived neurons), and three-dimensional cell cultures (e.g., minibrain models) have been, or could be, exposed to a variety of different anesthetic drugs, at a wide range of concentrations. Cell-based approaches have the advantage of ease, speed, and being highly mechanistic, but suffer from several limitations as listed below.…”

Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

“…Dexmedetomidine, a sedative α 2 -adrenergic receptor agonist, has been shown to reduce the incidence of delirium in patients [49]. Intriguingly, dexmedetomidine mitigates the anesthetic-induced increase in tonic current and prevents persistent behavioral deficit in a mouse model, through stimulation of the release of brain-derived neurotrophic factor [50]. Whether similar molecular mechanisms occur in humans remains an exciting area of future inquiry.…”