Department of Neurology, Xijing Hospital, Fourth Military Medical University, 17 Changle West Road, Xi'an 710032, China.
Pharmacol Biochem Behav. 2012 Dec;103(2):187-96. doi: 10.1016/j.pbb.2012.08.025. Epub 2012 Aug 31.
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. 24h after onset of status epilepticus (SE), the epileptic rats received saline or 1mg/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-1β) and tumor necrosis factor alpha (TNFα) 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-1β and TNFα 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 21-34days 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.
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，抗炎药物预防癫痫的疗效仍存在争议。芬戈莫德（FTY720）是一种鞘氨醇-1-磷酸（S1P）类似物，在多发性硬化症（MS）患者和动物模型中具有强大的抗炎作用。在这里，我们测试了 FTY720 是否可以在锂-匹罗卡品诱导的癫痫成年大鼠模型中发挥抗癫痫发生作用。癫痫发作后 24 小时（SE），癫痫大鼠接受生理盐水或 1mg/kg FTY720 腹腔注射，每天一次，连续 14 天。此后，在 SE 大鼠中评估了自发性惊厥（SCs）、苔藓纤维发芽（MFS）、神经元丢失、小胶质细胞和星形胶质细胞激活、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNFα）的表达。我们发现，FTY720 治疗可减少 SE 后 4 天海马神经元丢失，并减少小胶质细胞和星形胶质细胞的激活。同时，FTY720 治疗可抑制海马中异常表达的 IL-1β和 TNFα。此外，FTY720 治疗可通过增加海马神经元核（NeuN）阳性细胞和减少氟代-Jade B（FJB）阳性细胞来发挥神经保护作用。SE 后 21-34 天，与生理盐水治疗组相比，FTY720 治疗组大鼠的 SC 发生率、持续时间、频率和严重程度均显著降低。异常的 MFS 也被 FTY720 给药减轻。这些结果表明，FTY720 在锂-匹罗卡品癫痫模型中具有抗炎和抗癫痫发生作用，它可能为预防癫痫发生提供一种新的治疗方法。
