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
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.
CNS Neurosci Ther. 2025 Mar;31(3):e70215. doi: 10.1111/cns.70215.
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.
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.
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.
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.
人类和动物急性中毒有机磷酸酯索曼可引发持续性癫痫持续状态（SE），且该状态会迅速对苯二氮䓬类药物产生耐药性。我们在索曼诱导的SE大鼠模型中，比较了咪达唑仑（当前治疗有机磷中毒性SE的标准护理药物）与咪达唑仑和别孕烯醇酮（ALLO）联合治疗的抗癫痫疗效。
在癫痫发作开始20分钟后，对具有强烈癫痫行为和高振幅脑电图（EEG）活动的索曼中毒雄性大鼠注射咪达唑仑（0.65毫克，肌肉注射），10分钟后再注射第二剂咪达唑仑或ALLO（12或24毫克/千克，肌肉注射）。治疗后监测癫痫行为和EEG 4小时。监测期结束时收集大脑进行组织学分析。
接受两剂咪达唑仑的动物表现出持续性SE。先注射咪达唑仑再注射ALLO的序贯给药抑制了脑电图癫痫活动。与两剂咪达唑仑相比，联合治疗还显著减少了索曼诱导的神经退行性变和神经炎症。高剂量而非低剂量的ALLO在给药后1小时内与短暂且可逆的呼吸功能不全有关。
先注射咪达唑仑再注射ALLO的治疗方法在抑制苯二氮䓬类药物耐药的、索曼诱导的SE以及减轻其急性神经病理学后果方面比两剂咪达唑仑更有效。
