Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats
Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats
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DOI：
10.1016/j.neuropharm.2016.07.028
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发表时间：
2016-11-01
影响因子：
4.7
通讯作者：
Dingledine, Raymond
中科院分区：
文献类型：
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作者：
Rojas, Asheebo;Ganesh, Thota;Dingledine, Raymond
接触有机磷神经毒剂的幸存者可能会出现许多并发症，包括长期认知缺陷（Miyaki 等人，2005 年；Nishiwaki 等人，2001 年）。我们最近证明，抑制前列腺素 E2 受体 EP2 可以减轻由梭曼类似物二异丙基氟磷酸盐 (DFP) 诱导的癫痫持续状态 (SE) 引起的神经炎症和神经变性，这种情况在初次损伤后数小时至数天内就会显现。在这里，我们测试了这样的假设：DFP 暴露会导致大鼠认知功能丧失，而早期、短暂的 EP2 抑制会阻止这种丧失。相对于 DFP 诱导的 SE，在不同时间对成年雄性 Sprague-Dawley 大鼠施用载体或竞争性 EP2 拮抗剂 TG6-10-1（腹腔注射）。皮层脑电图 (EEG) 表明，DFP 给药导致癫痫发作时间延长。 DFP 前 1 小时单次腹腔注射 TG6-10-1 或载体不会改变癫痫发作的发展、SE 潜伏期或 SE 持续时间。在 DFP 诱导的 SE 发生后 90 分钟开始，对大鼠进行六次注射 TG6-10-1，可以在 SE 后 6-12 周区分新物体和熟悉物体，这与媒介物治疗的大鼠不同，后者对新物体没有表现出偏好。相比之下，明暗盒和开放场测定中的行为变化不受 TG6-10-1 的影响。 DFP 后的延迟死亡率也不受 TG6-10-1 的影响。因此，选择性抑制 EP2 受体可以预防因暴露于高剂量 DFP 引起的 SE 诱导的大鼠记忆损伤。 (C) 2016 Elsevier Ltd. 保留所有权利。
Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6-12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE induced memory impairment in rats caused by exposure to a high dose of DFP. (C) 2016 Elsevier Ltd. All rights reserved.