RESEARCH ARTICLE
Enhancement of Cortical GABAergic Function does not Account for the Anticonvulsant Effects of Midazolam, Isoflurane or Etomidate
Logan J. Voss*, James W. Sleigh
Article Information
Identifiers and Pagination:
Year: 2010Volume: 4
First Page: 5
Last Page: 12
Publisher ID: TOATJ-4-5
DOI: 10.2174/1874321801004010005
Article History:
Received Date: 19/11/2009Revision Received Date: 08/03/2010
Acceptance Date: 23/05/2010
Electronic publication date: 29/7/2010
Collection year: 2010
open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background:
Enhancement of cerebrocortical GABAergic inhibition is postulated as the main mechanism by which anesthetics inhibit seizures; however this has not been directly tested under controlled conditions. In this study we utilized the isolated cerebral cortex slice preparation and tested the anticonvulsant properties of three anesthetics with differing specificities for GABAergic activation and with various clinical and experimental anticonvulsant efficacy; midazolam, isoflurane and etomidate.
Methods:
Two interictal-like models were investigated; low-magnesium artificial cerebrospinal fluid (ACSF) and low dose (230nM) aconitine in low-magnesium ACSF. The former generates interictal-like events by facilitating NMDA activation and is well described in the cortical slice preparation; the latter generates a unique pattern of interictal-like activity by opening voltage-gated sodium channels.
Results:
We found that at anesthetic concentrations and above (15μM midazolam, 480μM isoflurane and 4μM etomidate), only isoflurane had an anticonvulsant effect. The isoflurane effect was seen as a reduction in event frequency in both models (56% reduction in low-magnesium and 26% reduction in aconitine, p < 0.005 and p < 0.05, respectively). Picrotoxin (100μM) was ineffective at blocking the isoflurane anticonvulsant effect (56% reduction in event frequency, p < 0.01). Picrotoxin (100μM) and bicuculline (25μM) administered on their own increased event frequency (107% and 75%, respectively, p < 0.005), indicating the GABAergic system was functional in the slice preparation.
Conclusion:
These results call into question the view that enhancement of cortical GABAergic function is the primary mechanism by which anesthetics suppress seizure activity.
