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Strain differences in the extent of brain injury in mice after tetramethylenedisulfotetramine-induced status epilepticus
NeuroToxicology ( IF 3.4 ) Pub Date : 2021-08-31 , DOI: 10.1016/j.neuro.2021.08.011
Jonas J Calsbeek 1 , Eduardo A González 1 , Casey A Boosalis 1 , Dorota Zolkowska 2 , Donald A Bruun 1 , Douglas J Rowland 3 , Naomi H Saito 4 , Danielle J Harvey 4 , Abhijit J Chaudhari 3 , Michael A Rogawski 2 , Joel R Garbow 5 , Pamela J Lein 1
Affiliation  

Acute intoxication with tetramethylenedisulfotetramine (TETS) can trigger status epilepticus (SE) in humans. Survivors often exhibit long-term neurological effects, including electrographic abnormalities and cognitive deficits, but the pathogenic mechanisms linking the acute toxic effects of TETS to chronic outcomes are not known. Here, we use advanced in vivo imaging techniques to longitudinally monitor the neuropathological consequences of TETS-induced SE in two different mouse strains. Adult male NIH Swiss and C57BL/6J mice were injected with riluzole (10 mg/kg, i.p.), followed 10 min later by an acute dose of TETS (0.2 mg/kg in NIH Swiss; 0.3 mg/kg, i.p. in C57BL/6J) or an equal volume of vehicle (10% DMSO in 0.9% sterile saline). Different TETS doses were administered to trigger comparable seizure behavior between strains. Seizure behavior began within minutes of TETS exposure and rapidly progressed to SE that was terminated after 40 min by administration of midazolam (1.8 mg/kg, i.m.). The brains of vehicle and TETS-exposed mice were imaged using in vivo magnetic resonance (MR) and translocator protein (TSPO) positron emission tomography (PET) at 1, 3, 7, and 14 days post-exposure to monitor brain injury and neuroinflammation, respectively. When the brain scans of TETS mice were compared to those of vehicle controls, subtle and transient neuropathology was observed in both mouse strains, but more extensive and persistent TETS-induced neuropathology was observed in C57BL/6J mice. In addition, one NIH Swiss TETS mouse that did not respond to the midazolam therapy, but remained in SE for more than 2 h, displayed robust neuropathology as determined by in vivo imaging and confirmed by FluoroJade C staining and IBA-1 immunohistochemistry as readouts of neurodegeneration and neuroinflammation, respectively. These findings demonstrate that the extent of injury observed in the mouse brain after TETS-induced SE varied according to strain, dose of TETS and/or the duration of SE. These observations suggest that TETS-intoxicated humans who do not respond to antiseizure medication are at increased risk for brain injury.



中文翻译:

四亚甲基二硫四胺致癫痫持续状态小鼠脑损伤程度的应变差异

四亚甲基二磺胺四胺 (TETS) 的急性中毒可引发人类癫痫持续状态(SE)。幸存者通常表现出长期的神经系统影响,包括电图异常和认知缺陷,但将 TETS 的急性毒性作用与慢性结果联系起来的致病机制尚不清楚。在这里,我们使用先进的体内成像技术纵向监测 TETS 诱导的 SE 在两种不同小鼠品系中的神经病理学后果。给成年雄性 NIH Swiss 和 C57BL/6J 小鼠注射利鲁唑 (10 mg/kg, ip),10 分钟后注射急性剂量的 TETS (NIH Swiss 0.2 mg/kg;0.3 mg/kg, ip in C57BL/ 6J) 或等体积的载体(10% DMSO 的 0.9% 无菌盐水)。施用不同的 TETS 剂量以引发菌株之间的类似癫痫发作行为。癫痫发作在 TETS 暴露数分钟内开始,并迅速发展为 SE,并在 40 分钟后通过咪达唑仑(1.8 mg/kg,im)给药终止。使用体内对载体和暴露于 TETS 的小鼠的大脑进行成像分别在暴露后 1、3、7 和 14 天进行磁共振 (MR) 和易位蛋白 (TSPO) 正电子发射断层扫描 (PET),以监测脑损伤和神经炎症。当将 TETS 小鼠的脑部扫描与载体对照进行比较时,在两种小鼠品系中都观察到了细微和短暂的神经病理学,但在 C57BL/6J 小鼠中观察到了更广泛和持久的 TETS 诱导的神经病理学。此外,一只对咪达唑仑治疗没有反应但在 SE 中停留超过 2 小时的 NIH 瑞士 TETS 小鼠表现出强健的神经病理学,如体内测定成像并通过 FluoroJade C 染色和 IBA-1 免疫组织化学分别确认为神经变性和神经炎症的读数。这些发现表明,在 TETS 诱导的 SE 后,在小鼠脑中观察到的损伤程度根据应变、TETS 的剂量和/或 SE 的持续时间而变化。这些观察结果表明,对抗癫痫药物没有反应的 TETS 中毒的人脑损伤的风险增加。

更新日期:2021-09-04
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