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.

• Authors: Dian-Shi Wang, Kirusanthy Kaneshwaran, Gang Lei, Fariya Mostafa, Junhui Wang, Irene Lecker, Sinziana Avramescu, Yu-Feng Xie, Nathan K Chan, Alejandro Fernandez-Escobar, Junsung Woo, Darren Chan, Amy J Ramsey, Jeremy M Sivak, C Justin Lee, Robert P Bonin, Beverley A Orser
• Journal: Anesthesiology (Anesthesiology) Vol. 129 Issue 3 Pg. 477-489 (09 2018) ISSN: 1528-1175 [Electronic] United States
• PMID: 29889105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-2 Receptor Agonists
• Anesthetics, Intravenous
• Gabra5 protein, mouse
• Hypnotics and Sedatives
• Receptors, GABA-A
• Dexmedetomidine
• Etomidate

Topics

• Adrenergic alpha-2 Receptor Agonists (pharmacology)
• Anesthetics, Intravenous (pharmacology)
• Animals
• Cells, Cultured
• Coculture Techniques
• Dexmedetomidine (pharmacology)
• Etomidate (pharmacology)
• Executive Function (drug effects, physiology)
• Hippocampus (cytology, drug effects, physiology)
• Humans
• Hypnotics and Sedatives (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, GABA-A (physiology)