Nguyen Donna A, Niquet Jerome, Marrero-Rosado Brenda, Schultz Caroline R, Stone Michael F, de Araujo Furtado Marcio, Biney Abiel K, Lumley Lucille A
Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen Proving Ground, MD, United States of America.
Department of Neurology, David Geffen School of Medicine at UCLA, Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States of America.
Exp Neurol. 2025 Mar;385:115122. doi: 10.1016/j.expneurol.2024.115122. Epub 2024 Dec 20.
Exposure to organophosphorus nerve agents irreversibly inhibits acetylcholinesterase and may lead to cholinergic crisis and seizures. Although benzodiazepines are the standard of care after nerve agent-induced status epilepticus, when treatment is delayed for up to 30 min or more, refractory status epilepticus can develop. Adult male rodents are often utilized for evaluation of therapeutic efficacy against nerve agent exposure. However, there may be age and sex differences in toxicity and in therapeutic response. We previously reported that juvenile rats are less susceptible to the lethal effects of soman compared to adults, while pups are the most susceptible. Here, we report on age and sex differences in delayed midazolam treatment efficacy on survival, seizures and brain pathology. Male and female pups, juvenile and adult rats were exposed to an equitoxic dose of soman and treated with atropine sulfate and the oxime asoxime chloride (HI-6 dimethanesulphonate) 1 min after exposure and with midazolam 40 min after seizure onset, determined by EEG in juvenile and adult rats, and by behavior in pups. Survival, seizure data, and spontaneous recurrent seizures were evaluated. Brains were processed to assess neurodegeneration, neuroinflammation, and blood brain barrier (BBB) integrity. Juvenile and adult rats exposed to soman and treated with midazolam had BBB disruption, epileptogenesis, neurodegeneration, microglial activation, and astrogliosis; adult rats had poorer outcomes. Pups and juvenile rats exposed to soman had poor survival prior to midazolam treatment but most survived once treated; overall, neurodegeneration or disrupted BBB integrity was not detected in midazolam-treated pups. We found that age is a determinant factor in soman-induced toxicity and response to standard medical countermeasures. In addition, we observed sex differences in response to soman in juveniles and males with respect to body weight growth curves and in neuronal loss in juveniles and adults. Adjunct therapies to midazolam are warranted and it is important to evaluate both age and sex as factors in therapeutic response.
接触有机磷神经毒剂会不可逆地抑制乙酰胆碱酯酶，并可能导致胆碱能危象和癫痫发作。尽管苯二氮䓬类药物是神经毒剂诱发癫痫持续状态后的标准治疗药物，但当治疗延迟长达30分钟或更长时间时，可能会发展为难治性癫痫持续状态。成年雄性啮齿动物常被用于评估针对神经毒剂暴露的治疗效果。然而，在毒性和治疗反应方面可能存在年龄和性别差异。我们之前报道过，与成年大鼠相比，幼年大鼠对梭曼的致死作用更不敏感，而幼崽最为敏感。在此，我们报告了咪达唑仑延迟治疗对生存、癫痫发作和脑病理学影响的年龄和性别差异。将雄性和雌性幼崽、幼年和成年大鼠暴露于等毒性剂量的梭曼中，并在暴露后1分钟用硫酸阿托品和肟类化合物氯解磷定（HI-6二甲磺酸盐）进行治疗，在癫痫发作开始后40分钟（幼年和成年大鼠通过脑电图测定，幼崽通过行为测定）用咪达唑仑进行治疗。评估生存情况、癫痫发作数据和自发性反复癫痫发作。对大脑进行处理以评估神经退行性变、神经炎症和血脑屏障（BBB）完整性。暴露于梭曼并接受咪达唑仑治疗的幼年和成年大鼠出现了血脑屏障破坏、癫痫发生、神经退行性变、小胶质细胞活化和星形胶质细胞增生；成年大鼠的预后较差。暴露于梭曼的幼崽和幼年大鼠在接受咪达唑仑治疗前生存率较低，但大多数在治疗后存活；总体而言，在接受咪达唑仑治疗的幼崽中未检测到神经退行性变或血脑屏障完整性破坏。我们发现年龄是梭曼诱导毒性和对标准医学对抗措施反应的决定因素。此外，我们观察到在幼年和成年大鼠中，幼年大鼠和雄性大鼠在体重生长曲线方面以及在神经元损失方面对梭曼的反应存在性别差异。有必要对咪达唑仑进行辅助治疗，并且将年龄和性别作为治疗反应的因素进行评估很重要。
