Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model.
Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model.
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DOI：
10.3389/fncel.2021.772868
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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;Putra M;Gomez-Estrada C;Golden M;Wachter L;Gard M;Thippeswamy T
急性有机磷酸盐（OP）中毒对军事和文职人员都构成了重大威胁，因为它可以导致各种胆碱能症状，包括癫痫持续状态（SE）的发展。根据其严重程度，SE可导致一系列神经系统变化，包括神经炎症和神经变性。在这项研究中，我们确定了SE严重程度和持续时间对神经胶质增生和神经退行性变等疾病促进参数的影响，以及疾病调节剂saracatini（AZD 0530）（一种Src/Fyn酪氨酸激酶抑制剂）的疗效。将动物暴露于4 mg/kg二异丙基氟磷酸盐（DFP，s.c.）然后是医疗对策我们有五个实验组：对照组（无DFP），无连续惊厥发作（CS）的动物，连续CS ≥ 20分钟的动物，连续CS 31-60分钟的动物，以及连续CS> 60分钟的动物。然后在DFP暴露后8天评估这些组的星形胶质细胞增生、小胶质细胞增生和神经变性。与对照组相比，31-60-min和> 60-min组（但非> 20-min组）在海马中具有显著上调的胶质增生和神经变性。然而，在梨状皮质和杏仁核中，所有三个连续CS组在神经胶质增生和神经退行性变中都有显著上调。在另一组连续CS <20分钟且> 60分钟的动物中，我们从DFP后3小时开始给药7天。无论初始SE严重程度和持续时间如何，均存在体重减轻和死亡。然而，在存活的动物中，saracatinib在两个严重程度组的第一周内均预防了自发性复发性癫痫发作（SRS）。在20分钟CS组中，与溶剂相比，saracatinib显著降低了梨状皮质和杏仁核的神经变性。未处理对照组和saracatinib自身（无DFP）组之间的测量参数无显著差异。总体而言，本研究证明了初始SE严重程度和持续时间对神经胶质增生和神经变性定位的差异影响。我们还证明了saracatinib的疾病修饰潜力。然而，其给药方案应根据SE期间CS的初始严重程度和持续时间进行优化，以在DFP模型以及其他OP模型（如梭曼）中最大化治疗效果并最小化毒性。
Acute organophosphate (OP) toxicity poses a significant threat to both military and civilian personnel as it can lead to a variety of cholinergic symptoms including the development of status epilepticus (SE). Depending on its severity, SE can lead to a spectrum of neurological changes including neuroinflammation and neurodegeneration. In this study, we determined the impact of SE severity and duration on disease promoting parameters such as gliosis and neurodegeneration and the efficacy of a disease modifier, saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor. Animals were exposed to 4 mg/kg diisopropylfluorophosphate (DFP, s.c.) followed by medical countermeasures. We had five experimental groups: controls (no DFP), animals with no continuous convulsive seizures (CS), animals with ∼20-min continuous CS, 31-60-min continuous CS, and > 60-min continuous CS. These groups were then assessed for astrogliosis, microgliosis, and neurodegeneration 8 days after DFP exposure. The 31-60-min and > 60-min groups, but not ∼20-min group, had significantly upregulated gliosis and neurodegeneration in the hippocampus compared to controls. In the piriform cortex and amygdala, however, all three continuous CS groups had significant upregulation in both gliosis and neurodegeneration. In a separate cohort of animals that had ∼20 and > 60-min of continuous CS, we administered saracatinib for 7 days beginning three hours after DFP. There was bodyweight loss and mortality irrespective of the initial SE severity and duration. However, in survived animals, saracatinib prevented spontaneous recurrent seizures (SRS) during the first week in both severity groups. In the ∼20-min CS group, compared to the vehicle, saracatinib significantly reduced neurodegeneration in the piriform cortex and amygdala. There were no significant differences in the measured parameters between the naïve control and saracatinib on its own (without DFP) groups. Overall, this study demonstrates the differential effects of the initial SE severity and duration on the localization of gliosis and neurodegeneration. We have also demonstrated the disease-modifying potential of saracatinib. However, its’ dosing regimen should be optimized based on initial severity and duration of CS during SE to maximize therapeutic effects and minimize toxicity in the DFP model as well as in other OP models such as soman.
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影响因子：
3.8
作者：
Fan Y;Xie L;Chung CY
通讯作者：
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影响因子：
5.3
作者：
Fernández-Arjona MDM;Grondona JM;Granados-Durán P;Fernández-Llebrez P;López-Ávalos MD
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作者：
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影响因子：
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作者：
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作者：
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通讯作者：
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