TY - JOUR
T1 - Dexmedetomidine prevents excessive γ-aminobutyric acid type a receptor function after anesthesia
AU - Wang, Dian Shi
AU - Kaneshwaran, Kirusanthy
AU - Lei, Gang
AU - Mostafa, Fariya
AU - Wang, Junhui
AU - Lecker, Irene
AU - Avramescu, Sinziana
AU - Xie, Yu Feng
AU - Chan, Nathan K.
AU - Fernandez-Escobar, Alejandro
AU - Woo, Junsung
AU - Chan, Darren
AU - Ramsey, Amy J.
AU - Sivak, Jeremy M.
AU - Lee, C. Justin
AU - Bonin, Robert P.
AU - Orser, Beverley A.
N1 - Funding Information:
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 Peri-operative Brain Health Centre, Toronto, Ontario, Canada (http://www.perioperativebrainhealth.com).
Publisher Copyright:
© 2018, the American Society of Anesthesiologists, Inc.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055933313&partnerID=8YFLogxK
U2 - 10.1097/ALN.0000000000002311
DO - 10.1097/ALN.0000000000002311
M3 - Article
C2 - 29889105
AN - SCOPUS:85055933313
SN - 0003-3022
VL - 129
SP - 477
EP - 489
JO - Anesthesiology
JF - Anesthesiology
IS - 3
ER -
