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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-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 21–34 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.▸ FTY720 attenuated neuronal loss, neuroinflammation at four days post-SE. ▸ FTY720 reduced the spontaneous convulsions during 21–34 days post-SE. ▸ FTY720 restrained aberrant mossy fiber sprouting at 35 days post-SE.