Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology.
Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology.
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DOI：
10.3389/fncel.2021.798247
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发表时间：
2021
影响因子：
5.3
通讯作者：
Thippeswamy T
中科院分区：
文献类型：
--
作者：
Gage M;Rao NS;Samidurai M;Putra M;Vasanthi SS;Meyer C;Wang C;Thippeswamy T
对有机磷神经毒剂(OPNA)暴露的真实场景进行建模是具有挑战性的。军事人员预先服用吡斯的明，这导致了OPNA模型的发展与吡斯的明/肟预处理，以研究新的治疗急性和慢性影响的方法。然而，平民没有预先服用吡斯的明/肟类药物。因此，没有吡斯的明的实验模型也被其他实验室开发出来，尽管通常只在男性身上进行。OPNA暴露后，长时间的惊厥发作(CS)或癫痫持续状态(SE)令人担忧。CS/SE的持续时间和严重程度决定了幸存者的脑损伤程度，即使在接受了药物对策(MCM)/解毒剂(如阿托品)和抗惊厥剂(如安定/咪达唑仑)治疗后也是如此。在这项研究中，使用大量的成年雄性和雌性大鼠的混合队列，在没有预先处理的情况下，82%的动物对梭曼(GD，132μg/kg，S.C.)有持续20分钟的严重SE。硫酸阿托品(2 mg/kg，肌肉注射)和HI-6(125 mg/kg，肌肉注射)分别于染毒后1h给予梭曼和咪达唑仑(3 mg/kg，i.m)。在平民接触平民的情况下，立即进行MCM治疗是不切实际的，但这种方法在实验模型中降低了死亡率。有趣的是，雌性大鼠，无论发情阶段，平均有44分钟的CS(阶段≥3)，而雄性在SE期间，从梭曼暴露于咪达唑仑开始，平均有32分钟的CS。然而，在植入遥测装置的组中，SE严重程度没有显著的性别差异；在使用咪达唑仑之前，男性持续CS时间为40分钟，女性为43分钟。在注射咪达唑仑之前没有动物死亡，只有不到5%的动物在梭曼中毒后的第一周死亡。在遥测动物中，脑电变化和实时行为发作之间存在直接关联。在长期随机选择的动物中，85%的动物观察到惊厥性自发性反复发作(SRS)。在梭曼4个月后，脑组织学证实反应性胶质增生和神经变性。这项研究的新发现是，在非遥测动物中，雌性梭曼中毒后的SE严重程度显著高于雄性，发情周期不影响反应。
Modeling a real-world scenario of organophosphate nerve agent (OPNA) exposure is challenging. Military personnel are premedicated with pyridostigmine, which led to the development of OPNA models with pyridostigmine/oxime pretreatment to investigate novel therapeutics for acute and chronic effects. However, civilians are not premedicated with pyridostigmine/oxime. Therefore, experimental models without pyridostigmine were developed by other laboratories though often only in males. Following OPNA exposure, prolonged convulsive seizures (CS) or status epilepticus (SE) are concerning. The duration and severity of CS/SE determine the extent of brain injury in survivors even after treating with medical countermeasures (MCM)/antidotes such as atropine, an oxime, and an anticonvulsant such as diazepam/midazolam. In this study, using a large mixed sex cohort of adult male and female rats, without pretreatment, we demonstrate severe SE lasting for >20 min in 82% of the animals in response to soman (GD,132 μg/kg, s.c.). Atropine sulfate (2 mg/kg, i.m.) and HI-6 (125 mg/kg, i.m.) were administered immediately following soman, and midazolam (3 mg/kg, i.m.) 1 h post-exposure. Immediate MCM treatment is impractical in civilian exposure to civilians, but this approach reduces mortality in experimental models. Interestingly, female rats, irrespective of estrous stages, had an average of 44 min CS (stage ≥ 3), while males had an average of 32 min CS during SE, starting from soman exposure to midazolam treatment. However, in telemetry device implanted groups, there were no significant sex differences in SE severity; males had 40 min and females 43 min of continuous CS until midazolam was administered. No animals died prior to midazolam administration and less than 5% died in the first week after soman intoxication. In telemetered animals, there was a direct correlation between EEG changes and behavioral seizures in real-time. In the long-term, convulsive spontaneously recurring seizures (SRS) were observed in 85% of randomly chosen animals. At 4-months post-soman, the brain histology confirmed reactive gliosis and neurodegeneration. The novel findings of this study are that, in non-telemetered animals, the SE severity following soman intoxication was significantly greater in females compared to males and that the estrous cycle did not influence the response.
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影响因子：
5.3
作者：
Gage M;Putra M;Gomez-Estrada C;Golden M;Wachter L;Gard M;Thippeswamy T
通讯作者：
Thippeswamy T
影响因子：
4.7
作者：
Auta, J;Costa, E;Guidotti, A
通讯作者：
Guidotti, A
影响因子：
4.3
作者：
Gotor, Raul;Costero, Ana M.;Sancenon, Felix
通讯作者：
Sancenon, Felix
DOI：
10.1124/jpet.114.217299
发表时间：
2014-11-01
影响因子：
3.5
作者：
Apland, James P.;Aroniadou-Anderjaska, Vassiliki;Braga, Maria F. M.
通讯作者：
Braga, Maria F. M.
影响因子：
3.4
作者：
Bruun, Donald A.;Guignet, Michelle;Lein, Pamela J.
通讯作者：
Lein, Pamela J.