Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
Neurobiol Dis. 2013 Nov;59:183-93. doi: 10.1016/j.nbd.2013.07.015. Epub 2013 Aug 9.
We studied whether pharmacological blockade of the IL-1β-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-1β 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-1β cleavage and release. Antiinflammatory drugs were given 60min after antiepileptic (AED) drug-controlled SE induced by pilocarpine, or 180min after unrestrained electrical SE, for 7days using a protocol yielding therapeutic drug levels in brain. This drug combination significantly decreased both IL-1β 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 3months 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 Toll-like receptors, both contributing to cell loss and seizure generation. We conclude that the IL-1β 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 co-treatment with AEDs, is likely to be required for optimizing beneficial outcomes.
我们研究了通过癫痫发作性损伤在大脑前快速激活的 IL-1β 介导的信号传导的药理学阻断是否在两种不同的癫痫持续状态 (SE) 大鼠模型中提供神经保护。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-1β 信号通过全身给予两种抗炎药物来阻断，即人重组 IL-1 受体拮抗剂（anakinra），一种天然存在的和临床上使用的竞争性 IL-1 受体 1 拮抗剂，和 VX-765 一种特异性非肽抑制剂，可抑制 IL-1β 的切割和释放。抗炎药物在癫痫发作性（AED）药物控制的匹鲁卡品诱导的 SE 后 60 分钟，或在不受约束的电 SE 后 180 分钟给予，持续 7 天，使用产生脑内治疗药物水平的方案。这种药物组合显著降低了星形胶质细胞中的 IL-1β 表达和大鼠前脑的细胞丢失。在电 SE 模型中，神经保护和抗炎作用更为明显。电 SE 后 3 个月癫痫发作的发作、发作频率和持续时间没有明显改变。海马转录组分析表明，联合治疗并未影响 SE 期间癫痫发生期间诱导的广泛炎症反应。特别是，该治疗并未预防补体系统和 Toll 样受体的诱导，这两者均有助于细胞丢失和发作产生。我们得出结论，IL-1β 信号代表减少 SE 后细胞丢失的重要靶点。这些数据突出了一类新的临床测试药物，可在延迟损伤后干预时提供神经保护。在 SE 期间，更早地阻断这种快速起始的炎症途径，或同时用针对 SE 广泛炎症反应的其他成分的抗炎药物治疗，或与 AED 联合治疗，可能需要优化有益的结果。
