Enhancement of Cortical GABAergic Function does not Account for the Anticonvulsant Effects of Midazolam, Isoflurane or Etomidate~!2009-11-19~!2010-05-23~!2010-07-29~!

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 (15 M midazolam, 480 M isoflurane and 4 M 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 (100 M) was ineffective at blocking the isoflurane anticonvulsant effect (56% reduction in event frequency, p<0.01). Picrotoxin (100 M) and bicuculline (25 M) 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.

A Metabolic Mechanism for Anaesthetic Suppression of Cortical Synaptic Function in Mouse Brain Slices—A Pilot Investigation

“…For this study, the sevoflurane amount was doubled to account for its MAC value being twice that of isoflurane. The effect on SLE activity was qualitatively identical to that of isoflurane (see Figure 7 and [30]), confirming approximate 1MAC equivalence. The concentration of rotenone (1.5 µM) was chosen following a pilot study showing that this dose effected an increase in tissue oxygen, along with quantifiable, but not complete, suppression of SLE activity.…”

Connexin36 Gap Junction Blockade Is Ineffective at Reducing Seizure-Like Event Activity in Neocortical Mouse Slices

“…A nano-molar concentration of aconitine induces a unique pattern of persistent seizure-like activity in the cortical slice preparation [ 15 ]. Neocortical seizure-like activity of both low magnesium and aconitine is sensitive to the anticonvulsant effects of phenytoin (data not shown) and some anaesthetics [ 16 ], and therefore they both represent valid models for investigating seizure mechanisms.…”