Time-dependent reduction in the anticonvulsant effectiveness of diazepam against soman-induced seizures in guinea pigs

Abstract

Near-lethal exposure to nerve agents produces prolonged epileptiform seizures requiring the administration of benzodiazepine anticonvulsant drugs, such as diazepam. Clinically, benzodiazepines are reported to lose anticonvulsant effectiveness the greater the delay between seizure onset and benzodiazepine treatment. This time-dependent diminished effectiveness of diazepam was tested in the present study. Seizures elicited by the nerve agent, soman, were produced in guinea pigs instrumented to record brain electrocorticographic (ECoG) activity. Different groups of animals were administered 10 mg/kg, intramuscularly, of diazepam at 5, 40, 60, 80, or 160 minutes after the onset of seizure activity. There was a progressive loss in the anticonvulsant efficacy of diazepam as the treatment was delayed after seizure onset, but no differences in the time for diazepam to stop seizures. The results show a diminished ability of diazepam to stop nerve-agent–induced seizures the longer treatment is delayed.

Keywords::

• Nerve agent
• soman
• seizure
• diazepam
• benzodiazepine
• anticonvulsant

Acknowledgements

The authors wish to recognize the excellent technical assistance of Ms. Tami C. Rowland, Ms. Megan E. Lyman, Mr. Jacob W. Skovira, and Mr. John C. LaMont.

This research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adhered to the principles stated in The Guide for the Care and Use of Laboratory Animals, published by the National Research Council in 1996. The facility where this research was conducted is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense. This work has not been published elsewhere, nor has it been submitted simultaneously for publication elsewhere.

Declaration of interest

This research was supported by the Defense Threat Reduction Agency–Joint Science and Technology Office, Medical S&T Division: Proposal I.30004_04_RC_C. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.