Perampanel Reduces the Effects of Benzodiazepine-refractory Status Epilepticus in a Delayed Treatment Rat Model of Soman Exposure
Abstract number :
2.474
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2024
Submission ID :
1382
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Lucille Lumley, PhD – US Army Medical Research Institute of Chemical Defense
Jerome Niquet, PhD – UCLA
Donna Nguyen, BS – US Army Medical Research Institute of Chemical Defense
Caroline Schultz, BS – US Army Medical Research Institute of Chemical Defense
Michael Stone, BS – US Army Medical Research Institute of Chemical Defense
Abiel Biney, BS – US Army Medical Research Institute of Chemical Defense
Marcio de Araujo Furtado, PhD – BioSEaD, LLC
Claude Wasterlain, MD – UCLA
Rationale: The current standard medical countermeasures (MCM) against organophosphorus nerve agent (OPNA) exposure are atropine sulfate, an oxime reactivator, and a benzodiazepine (diazepam or midazolam). While effective at stopping OPNA-induced status epilepticus (SE) when administered shortly after onset, preclinical studies show that benzodiazepines are ineffective in stopping acute seizures and preventing the development of spontaneous recurrent seizures when treatment is delayed up to 30 min after exposure. Therapeutic adjuncts to midazolam are urgently needed in a delayed treatment scenario of OPNA exposure. In this study, we evaluated the AMPA receptor antagonist perampanel for efficacy as a second-line anti-seizure medication 20 min following midazolam administration, in treating soman-induced benzodiazepine-refractory SE.
Methods: Adult male Sprague-Dawley rats were exposed to 1.2 LD50 soman to induce SE, and EEG was recorded continuously for 2 weeks. Midazolam (3 mg/kg; ip) was injected 40 min after seizure onset. Perampanel (4 mg/kg; ip) or vehicle was injected 60 min after seizure onset (20 min after midazolam). Seizure data analyzed included time spent in seizure during the first 24h post-exposure, EEG power integral during SE and multiple post-treatment timepoints, as well as the incidence and frequency of spontaneous recurrent seizures.
Results: EEG power integral: In soman exposed rats, perampanel, administered 20 min after midazolam, significantly reduced the EEG power integral over the 1 h post-treatment period when compared to midazolam alone (p< 0.001). Perampanel also significantly reduced the EEG power integral over the 6 h post-treatment period when compared to midazolam alone (p< 0.001).
Seizure duration: Perampanel lowered the average seizure duration during the first 24 hours following GD exposure compared with midazolam monotherapy (p< 0.05).
Spontaneous recurrent seizure (SRS): Rats treated with perampanel had reduced incidence of SRS compared to those treated with midazolam alone (p< 0.05). In addition, rats treated with perampanel had reduced number of SRS following GD exposure compared with midazolam monotherapy (p< 0.05).
Anti-seizure Medications