Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats

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.

doi:10.1111/cns.70215

Title: Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats

Journal Article · 27 February 2025 · CNS Neuroscience & Therapeutics

DOI: https://doi.org/10.1111/cns.70215 · OSTI ID:2526659

Andrew, Peter M. ^[1]; MacMahon, Jeremy A. ^[1]; Liu, Xiuzhen ^[1]; Saito, Naomi H. ^[2]; Berger, Kyle E. ^[3]; Morgan, Julia E. ^[3]; Dhir, Ashish ^[4]; Harvey, Danielle J. ^[2]; McCarren, Hilary S. ^[3];

^[5];

^[1]

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

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.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: SC0014664

OSTI ID:: 2526659

Journal Information:: CNS Neuroscience & Therapeutics, Journal Name: CNS Neuroscience & Therapeutics Journal Issue: 3 Vol. 31; ISSN 1755-5930

Publisher:: Wiley-BlackwellCopyright Statement

Country of Publication:: Country unknown/Code not available

Language:: English

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