Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T characteristics. This study supports the utility of T mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.

中文翻译：

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基于定量 T2 图谱的大鼠急性有机磷中毒后脑损伤和治疗性救援的纵向评估

有机磷酸酯 (OP) 胆碱酯酶抑制剂的急性中毒会造成重大的公共健康风险。虽然目前批准的医疗对策可以提高生存率，但它们往往无法预防慢性神经损伤。因此，需要开发有效的疗法和定量指标来评估 OP 引起的脑损伤以及通过这些疗法进行的救援。在这项研究中，我们使用了 OP、二异丙基氟磷酸盐 (DFP) 急性中毒的大鼠模型来检验以下假设：从脑部磁共振成像 (MRI) 扫描获得的 T 测量可提供脑损伤和治疗效果的定量指标。成年雄性 Sprague Dawley 大鼠在暴露于 DFP 或媒介物 (VEH) 后 3、7 和 28 天，在接受或不接受标准抗癫痫药物咪达唑仑 (MDZ) 治疗后，在 7T MRI 扫描仪上进行成像；一种新型抗癫痫药物，四氢孕酮 (ALLO)；或 MDZ 和 ALLO (DUO) 联合治疗。我们的结果表明，DFP 暴露动物的平均 T 值是：（1）第 3 天所有感兴趣体积（VOIs）均高于 VEH； (2)随时间减少； (3) 第 28 天时丘脑下降。与未治疗的 DFP 动物相比，第 3 天时用 ALLO 或 DUO 治疗（而非单独使用 MDZ）显着降低了梨状皮质中的平均 T 值。在第 28 天，DUO 组显示出最有利的 T 特性。这项研究支持 T 映射在纵向监测脑损伤中的应用，并强调了 ALLO 作为辅助疗法来减轻与急性 OP 中毒相关的慢性发病率的治疗潜力。