Peng Weifeng, Shen Yijun, Wang Qiang, Ding Jing, Wang Xin
Department of Neurology, Zhongshan Hospital, Fudan University, Fenglin Road, Shanghai 200032, China.
Department of The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Brain Sci. 2021 Nov 5;11(11):1465. doi: 10.3390/brainsci11111465.
Epileptogenesis may be responsible for both of recurrent seizures and comorbid depression in epilepsy. Disease-modifying treatments targeting the latent period before spontaneous recurrent seizures may contribute to the remission of seizures and comorbid depression. We hypothesized that pre-treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase (sEH) inhibitor, which has anti-inflammatory and neuroprotective effects might rescue status epilepticus (SE)-induced dendritic spine loss and alleviate depressive behaviours. Rats were either pre-treated with TPPU (0.1 mg/kg/d) intragastrically or with vehicle (40% polyethylene glycol 400) from 7 days before to 7 days after SE that was induced with lithium chloride and pilocarpine intraperitoneally. Rats in the Control group were given saline instead. The forced swim test (FST) was performed on the 8th day after SE to evaluate the depression-like behaviours in rats. The results showed that seizures severity during SE was significantly decreased, and the immobility time during FST was significantly increased through TPPU pre-treatment. Moreover, pre-treatment with TPPU attenuated inflammations including microglial gliosis and the level of proinflammatory cytokine IL-1β in the hippocampus; in addition, neuronal and dendritic spine loss in the subfields of hippocampus was selectively rescued, and the expression of NR1 subunit of N-methyl-D-aspartate (NMDA) receptor, ERK1/2, CREB, and their phosphorylated forms involved in the dendritic spine development were all significantly increased. We concluded that pre-treatment with TPPU attenuated seizures severity during SE and depressive behaviours during the period of epileptogenesis probably by rescuing dendritic spine loss in the hippocampus.
癫痫发生可能是癫痫复发和共病抑郁的原因。针对自发性癫痫复发前潜伏期的疾病修饰治疗可能有助于癫痫发作和共病抑郁的缓解。我们假设，用具有抗炎和神经保护作用的可溶性环氧化物水解酶（sEH）抑制剂1-三氟甲氧基苯基-3-（1-丙酰基哌啶-4-基）脲（TPPU）进行预处理，可能挽救癫痫持续状态（SE）诱导的树突棘丢失并减轻抑郁行为。从SE诱导前7天至诱导后7天，大鼠分别接受TPPU（0.1mg/kg/d）灌胃预处理或赋形剂（40%聚乙二醇400）预处理。对照组大鼠给予生理盐水。在SE后第8天进行强迫游泳试验（FST），以评估大鼠的抑郁样行为。结果显示，通过TPPU预处理，SE期间的癫痫发作严重程度显著降低，FST期间的不动时间显著增加。此外，TPPU预处理减轻了包括小胶质细胞增生和海马中促炎细胞因子IL-1β水平在内的炎症；此外，选择性挽救了海马亚区的神经元和树突棘丢失，并且参与树突棘发育的N-甲基-D-天冬氨酸（NMDA）受体NR1亚基、ERK1/2、CREB及其磷酸化形式的表达均显著增加。我们得出结论，TPPU预处理可能通过挽救海马中的树突棘丢失，减轻了SE期间的癫痫发作严重程度和癫痫发生期间的抑郁行为。
