Abstract
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.
Highlights
Epileptogenesis might occur in the “latent period”, which mimics the human temporal lobe epilepsy, for example, status epilepticus (SE) caused by acute brain injury or febrile convulsions in young children followed by recurrent seizures in their later lives [6]
We proposed that the dendritic spine loss in the period of epileptogenesis might be caused by the inflammations, which was supported by the evidence that inflammations such as lipopolysaccharides exposure, viral immune activation, and prolonged exposure to inflammatory extracellular vesicles led to a significant decrease in dendritic spine density in hippocampal neurons and hippocampal slices in vivo and vitro [34,35,36]
We proposed that pretreatment with trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) might resolve the inflammations provoked by SE and rescued the spine loss in the hippocampus of LiCl-pilocarpine-induced rat SE model, which was expected to be involved in the mechanism of anti-depressant effect of TPPU, as dendritic spine loss was responsible for depressive behaviours in the depression animal models [22]
Summary
Epilepsy is a chronic brain disease characterized by abnormal hyperexcitability of neurons that may cause structural and functional network damages of the brain [1]. 25–75% of patients with epilepsy have neuropsychiatric comorbidities such as depression which is much more higher than non-epileptic controls [3]. The overlapping functional network between epilepsy and depression indicates the process of epileptogenesis may be responsible for the occurrence of recurrent seizures and comorbid depression in epilepsy [3,4]. The term epileptogenesis refers to the process by which a normal brain becomes epileptic. Epileptogenesis might occur in the “latent period”, which mimics the human temporal lobe epilepsy, for example, SE caused by acute brain injury or febrile convulsions in young children followed by recurrent seizures in their later lives [6]. Disease-modifying drugs targeting the latent period after SE may contribute to the remission of seizures and comorbidities
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