Fingolimod (FTY720) inhibits neuroinflammation and attenuates spontaneous convulsions in lithium-pilocarpine induced status epilepticus in rat model
Fingolimod (FTY720) inhibits neuroinflammation and attenuates spontaneous convulsions in lithium-pilocarpine induced status epilepticus in rat model
复制标题
芬戈莫德 (FTY720) 抑制锂-毛果芸香碱诱导的大鼠癫痫持续状态模型中的神经炎症并减轻自发性惊厥
DOI：
10.1016/j.pbb.2012.08.025
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发表时间：
2012-12-01
影响因子：
3.6
通讯作者：
Jiang, Wen
中科院分区：
文献类型：
--
作者：
Gao, Fei;Liu, Yangfeng;Jiang, Wen
越来越多的证据表明，神经炎症在癫痫发生中起着关键作用。然而，抗炎药预防癫痫的有效性仍然存在争议。Fingolimod（FTY 720）是一种鞘氨醇-1-磷酸（S1 P）类似物，在多发性硬化（MS）患者和动物模型中具有有效的抗炎作用。在这里，我们测试FTY 720是否可以发挥抗癫痫作用的成年大鼠模型锂-匹罗卡品诱导的癫痫。在癫痫持续状态（SE）发作后24 h，癫痫大鼠接受生理盐水或1 mg/kg FTY 720 i. p.，每天一次，连续14天。随后出现自发性惊厥（SC）。苔藓纤维发芽（MFS）、神经元损失、小胶质细胞和星形胶质细胞的活化。在SE大鼠中评估白细胞介素-1 β（IL-1 β）和肿瘤坏死因子α（TNF α）的表达。我们发现，FTY 720治疗减少了神经元的损失和减少激活的小胶质细胞和星形胶质细胞在海马在SE后四天。同时，FTY 720还抑制了海马区IL-1 β和TNF α的异常表达。此外，FTY 720的神经保护作用通过增加海马中的神经元核（NeuN）阳性细胞和减少Fluoro-Jade B（FJB）阳性细胞来证明。在SE后21-34天期间，与盐水处理的大鼠相比，FTY 720处理的大鼠中SC的发生率、持续时间、频率和严重程度显著降低。异常MFS也通过FTY 720施用而减弱。提示FTY 720在锂-匹罗卡品致痫模型中具有抗炎和抗癫痫作用，为癫痫的预防提供了新的治疗途径。(C)2012 Elsevier Inc. All rights reserved.
Accumulating evidence has shown that neuroinflammation plays a key role in epileptogenesis. However, the efficacy of anti-inflammatory agents for preventing epilepsy remains controversial. Fingolimod (FTY720), a sphingosine-1-phosphate (S1P) analog, has potent anti-inflammatory effects in multiple sclerosis (MS) patients and animal models. Here, we tested whether FTY720 could exert antiepileptogenic effects in an adult rat model of lithium-pilocarpine induced epilepsy. 24 h after onset of status epilepticus (SE), the epileptic rats received saline or 1 mg/kg FTY720 i.p. once daily for 14 consecutive days. Thereafter, spontaneous convulsions (SCs). mossy fiber sprouting (MFS), neuronal loss, activation of microglia and astrocytes. expressions of interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) were evaluated in the SE rats. We found that FTY720 treatment reduced neuronal loss and decreased activation of microglia and astrocytes in hippocampus at four days post-SE. Simultaneously, abnormal expressions of IL-1 beta and TNF alpha in hippocampus were restrained by FTY720 treatment. In addition, neuroprotective effects of FTY720 were demonstrated by increasing neuronal nuclei (NeuN)-positive cells and decreasing Fluoro-Jade B (FJB)-positive cells in the hippocampus. During 21-34 days post-SE, the incidence, duration, frequency and severity of SCs significantly decreased in FTY720 treated rats compared with saline treated rats. Aberrant MFS was also attenuated by FTY720 administration. These results suggest that FTY720 exerts anti-inflammatory and antiepileptogenic effects in lithium-pilocarpine model of epilepsy and it may provide a new therapeutic approach for prevention of epileptogenesis. (C) 2012 Elsevier Inc. All rights reserved.