U.S. Department of Energy Office of Scientific and Technical Information
Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats
Department of Molecular Biosciences University of California, Davis Davis California USA
Department of Public Health Sciences, School of Medicine University of California, Davis Davis California USA
Neuroscience Department, Medical Toxicology Research Division US Army Medical Research Institute of Chemical Defense Aberdeen Maryland USA
Department of Neurology, School of Medicine University of California, Davis Sacramento California USA
Department of Neurology, School of Medicine University of California, Davis Sacramento California USA, Department of Pharmacology, School of Medicine University of California, Davis Sacramento California USA
Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP‐induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman‐induced SE.
Methods
Soman‐intoxicated male rats with robust seizure behavior and high‐amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses.
Results
Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure activity. The combination therapy also significantly reduced soman‐induced neurodegeneration and neuroinflammation compared to 2 doses of midazolam. High but not low dose ALLO was associated with transitory and reversible respiratory compromise during the 1 h period after dosing.
Conclusions
Treatment with midazolam followed by ALLO was more effective than 2 doses of midazolam in suppressing benzodiazepine‐refractory, soman‐induced SE, and in mitigating its acute neuropathological consequences.
Andrew, Peter M., et al. "Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats." CNS Neuroscience & Therapeutics, vol. 31, no. 3, Feb. 2025. https://doi.org/10.1111/cns.70215
Andrew, Peter M., MacMahon, Jeremy A., Liu, Xiuzhen, Saito, Naomi H., Berger, Kyle E., Morgan, Julia E., Dhir, Ashish, Harvey, Danielle J., McCarren, Hilary S., Rogawski, Michael A., & Lein, Pamela J. (2025). Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats. CNS Neuroscience & Therapeutics, 31(3). https://doi.org/10.1111/cns.70215
Andrew, Peter M., MacMahon, Jeremy A., Liu, Xiuzhen, et al., "Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats," CNS Neuroscience & Therapeutics 31, no. 3 (2025), https://doi.org/10.1111/cns.70215
@article{osti_2526659,
author = {Andrew, Peter M. and MacMahon, Jeremy A. and Liu, Xiuzhen and Saito, Naomi H. and Berger, Kyle E. and Morgan, Julia E. and Dhir, Ashish and Harvey, Danielle J. and McCarren, Hilary S. and Rogawski, Michael A. and others},
title = {Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats},
annote = {ABSTRACT Aims Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP‐induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman‐induced SE. Methods Soman‐intoxicated male rats with robust seizure behavior and high‐amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses. Results Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure activity. The combination therapy also significantly reduced soman‐induced neurodegeneration and neuroinflammation compared to 2 doses of midazolam. High but not low dose ALLO was associated with transitory and reversible respiratory compromise during the 1 h period after dosing. Conclusions Treatment with midazolam followed by ALLO was more effective than 2 doses of midazolam in suppressing benzodiazepine‐refractory, soman‐induced SE, and in mitigating its acute neuropathological consequences. },
doi = {10.1111/cns.70215},
url = {https://www.osti.gov/biblio/2526659},
journal = {CNS Neuroscience & Therapeutics},
issn = {ISSN 1755-5930},
number = {3},
volume = {31},
place = {Country unknown/Code not available},
publisher = {Wiley-Blackwell},
year = {2025},
month = {02}}