Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus.
Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus.
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DOI：
10.1016/j.neuropharm.2015.01.017
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发表时间：
2015-06
影响因子：
4.7
通讯作者：
Dingledine R
中科院分区：
文献类型：
--
作者：
Rojas A;Ganesh T;Lelutiu N;Gueorguieva P;Dingledine R
暴露于高水平的有机磷化合物（OP）可通过急性胆碱能毒性诱导人类和啮齿动物的癫痫持续状态（SE），导致神经变性和脑炎症。目前没有治疗与OP暴露相关的神经病理学。我们最近证明，在匹鲁卡品诱导的SE小鼠中，对PGE 2的EP 2受体的抑制可减少神经元损伤。在这里，我们研究了EP 2抑制剂（TG 6 -10-1）在使用氟磷酸二异丙酯（DFP）的SE大鼠模型中的治疗效果。我们测试了这样的假设，即在DFP诱导的SE发作后很好地启动EP 2受体抑制，减少了相关的神经病理学。成年雄性SD大鼠皮下注射溴化吡啶斯的明（0.1mg/kg）和甲基溴化阿托品（20 mg/kg），然后腹腔注射DFP（9.5mg/kg）诱导SE。DFP给药导致考克斯-2的延长上调。在相对于DFP暴露的不同时间点向大鼠施用TG 6 -10-1或媒介物（ip）。用TG 6 -10-1或媒介物处理不改变所观察到的行为癫痫发作，然而，在DFP诱导的SE发作后80-150分钟开始的6个剂量的TG 6 -10-1显著减少海马中的神经变性，减弱炎性细胞因子爆发，减少小胶质细胞活化，并且在癫痫持续状态后的数天内减少体重减轻。相比之下，星形胶质细胞增生不受EP 2抑制4天后DFP。在DFP前1小时或DFP后4小时开始用EP 2拮抗剂进行短暂治疗无效。延迟死亡率在DFP后较低（10%），不受TG 6 -10-1的影响。因此，在与DFP诱导环氧合酶-2相一致的时间窗内选择性抑制EP 2受体具有神经保护作用并加速大鼠的功能恢复。
Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague-Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80-150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats.
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影响因子：
5.3
作者：
Borges, K;Gearing, M;Dingledine, R
通讯作者：
Dingledine, R
影响因子：
3.3
作者：
Nelson, TE;Gruol, DL
通讯作者：
Gruol, DL
影响因子：
6.1
作者：
Lee, Boyoung;Dziema, Heather;Obrietan, Karl
通讯作者：
Obrietan, Karl
影响因子：
3.4
作者：
Chapman, S;Kadar, T;Gilat, E
通讯作者：
Gilat, E
影响因子：
3.8
作者：
Li, Yonggang;Lein, Pamela J.;Liu, Cuimei;Bruun, Donald A.;Giulivi, Cecilia;Ford, Gregory D.;Tewolde, Teclemichael;Ross-Inta, Catherine;Ford, Byron D.
通讯作者：
Ford, Byron D.