Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy
Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy
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DOI：
10.1016/j.nbd.2013.07.015
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发表时间：
2013-11-01
影响因子：
6.1
通讯作者：
Vezzani, A.
中科院分区：
文献类型：
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作者：
Noe, F. M.;Polascheck, N.;Vezzani, A.
我们研究了是否药理学阻断IL-1 β介导的信号，迅速激活前脑癫痫损伤，提供神经保护在两个不同的大鼠模型癫痫持续状态（SE）。作为次要结果，我们测量了治疗对SE诱导的癫痫发生的影响。IL-1 β信号传导通过全身给予两种抗肿瘤药物阻断，即人重组IL-1受体拮抗剂（阿那白滞素），天然存在和临床使用的竞争性IL-1受体1型拮抗剂和VX-765，IL-1 β裂解和释放的特异性非肽抑制剂。抗炎药物给药后60分钟的抗癫痫（AED）药物控制的毛果芸香碱诱导SE，或180分钟后，无限制的电SE，7天使用的协议产生治疗药物的水平在大脑中。该药物组合显著降低星形胶质细胞中的IL-1 β表达和大鼠前脑中的细胞损失。在电SE模型中，神经保护作用和抑制作用更为明显。癫痫发作，频率和持续时间3个月后，电SE没有显着修改。海马中的转录组学分析表明，联合治疗不影响癫痫发生过程中SE诱导的广泛炎症反应。特别是，治疗并没有阻止补体系统和Toll样受体的诱导，这两个都有助于细胞损失和癫痫generation.We的结论是，IL-1 β信号转导是一个重要的目标，减少SE后细胞损失。这些数据突出了一类新的临床测试药物，在延迟的损伤后干预后提供神经保护。在SE期间，可能需要更早阻断这种快速发作的炎症通路，或与靶向SE广泛炎症反应的其他成分的抗癫痫药物联合治疗，或与AED联合治疗，以优化有益结局。(C)2013 Elsevier Inc. All rights reserved.
We studied whether pharmacological blockade of the IL-1 beta-mediated signaling, rapidly activated in forebrain by epileptogenic injuries, affords neuroprotection in two different rat models of status epilepticus (SE). As secondary outcome, we measured treatment's effect on SE-induced epileptogenesis. IL-1 beta signaling was blocked by systemic administration of two antiinflammatory drugs, namely human recombinant IL-1 receptor antagonist (anakinra), the naturally occurring and clinically used competitive IL-1 receptor type 1 antagonist and VX-765 a specific non-peptide inhibitor of IL-1 beta, cleavage and release. Antiinflammatory drugs were given 60 min after antiepileptic (AED) drug-controlled SE induced by pilocarpine, or 180 min after unrestrained electrical SE, for 7 days using a protocol yielding therapeutic drug levels in brain. This drug combination significantly decreased both IL-1 beta expression in astrocytes and cell loss in rat forebrain. Neuroprotection and the antiinflammatory effect were more pronounced in the electrical SE model. Onset of epilepsy, and frequency and duration of seizures 3 months after electrical SE were not significantly modified. Transcriptomic analysis in the hippocampus showed that the combined treatment did not affect the broad inflammatory response induced by SE during epileptogenesis. In particular, the treatment did not prevent the induction of the complement system and Tolllike receptors, both contributing to cell loss and seizure generation.We conclude that the IL-1 beta signaling represents an important target for reducing cell loss after SE. The data highlight a new class of clinically tested agents affording neuroprotection after a delayed post-injury intervention. Earlier blockade of this rapid onset inflammatory pathway during SE, or concomitant treatment with antiinflammatory drugs targeting additional components of the broad inflammatory response to SE, or cotreatment with AEDs, is likely to be required for optimizing beneficial outcomes. (C) 2013 Elsevier Inc. All rights reserved.