Midazolam is effective to reduce cortical network activity in organotypic cultures during severe cholinergic overstimulation with soman.

Abstract

Intoxication with organophosphorus compounds can result in life-threatening organ dysfunction and refractory seizures. Sedation or hypnosis is essential to facilitate mechanical ventilation and control seizure activity. The range of indications for midazolam includes both hypnosis and seizure control. Since benzodiazepines cause sedation and hypnosis by dampening neuronal activity of the cerebral cortex, we investigated the drug's effect on action potential firing of cortical neurons in brain slices. Extensive cholinergic overstimulation was induced by increasing acetylcholine levels and simultaneously treating the slices with soman to block acetylcholinesterase activity. At control conditions midazolam reduced discharge rates (median/95% confidence interval) from 8.8 (7.0-10.5) Hz (in the absence of midazolam) to 2.2 (1.4-2.9) Hz (10 μM midazolam) and 1.6 (0.9-2.2) Hz (20 μM midazolam). Without midazolam, cholinergic overstimulation significantly enhanced neuronal activity to 13.1 (11.0-15.2) Hz. Midazolam attenuated firing rates during cholinergic overstimulation to 6.5 (4.8-8.2) Hz (10 μM midazolam) and 4.1 (3.3-6.0) Hz (20 μM midazolam), respectively. Thus, high cholinergic tone attenuated the drug's efficacy only moderately. These results suggest that midazolam is worth being tested as a promising drug to induce sedation and hypnosis in patients suffering from severe organophosphorous intoxication.

• Authors: Berthold Drexler, Thomas Seeger, Franz Worek, Horst Thiermann, Bernd Antkowiak, Christian Grasshoff
• Journal: Toxicology letters (Toxicol Lett) Vol. 297 Pg. 19-23 (Nov 2018) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 30165091 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• GABA Modulators
• Soman
• Acetylcholine
• Midazolam

Topics

• Acetylcholine (metabolism)
• Action Potentials (drug effects)
• Animals
• Autonomic Nervous System Diseases (chemically induced, drug therapy)
• Cerebral Cortex (drug effects)
• Cholinesterase Inhibitors (toxicity)
• Electrophysiological Phenomena (drug effects)
• GABA Modulators (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Midazolam (pharmacology)
• Nerve Net (drug effects)
• Organ Culture Techniques
• Soman (antagonists & inhibitors, toxicity)
• Stimulation, Chemical