Akt Inhibitor Perifosine Prevents Epileptogenesis in a Rat Model of Temporal Lobe Epilepsy  

作　　者：Feng Zhu Jiejing Kai Linglin Chen Meiling Wu Jingyin Dong Qingmei Wang Ling-Hui Zeng 

机构地区：[1]Department of Clinical Medicine, School of Medicine,Zhejiang University City College [2]Department of Pharmacology, Zhejiang University School of Medicine

出　　处：《Neuroscience Bulletin》2018年第2期283-290,共8页神经科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81371429);the Public Welfare Technology Application Research Project of Zhejiang Province,China(2016C33211);the Science and Technology Commission of Hangzhou Municipality,Zhejiang Province,China(20140633B37and 20160533B73)

摘　　要：Accumulating data have revealed that abnormal activity of the mTOR(mammalian target of rapamycin)pathway plays an important role in epileptogenesis triggered by various factors. We previously reported that pretreatment with perifosine, an inhibitor of Akt(also called protein kinase B), abolishes the rapamycin-induced paradoxical increase of S6 phosphorylation in a rat model induced by kainic acid(KA). Since Akt is an upstream target in the mTOR signaling pathway, we set out to determine whether perifosine has a preventive effect on epileptogenesis. Here, we explored the effect of perifosine on the model of temporal epilepsy induced by KA in rats and found that pretreatment with perifosine had no effect on the severity or duration of the KA-induced status epilepticus. However, perifosine almost completely inhibited the activation of p-Akt and p-S6 both acutely and chronically following the KA-induced status epilepticus.Perifosine pretreatment suppressed the KA-induced neuronal death and mossy fiber sprouting. The frequency of spontaneous seizures was markedly decreased in rats pretreated with perifosine. Accordingly, rats pretreated with perifosine showed mild impairment in cognitive functions. Collectively, this study provides novel evidence in a KA seizure model that perifosine may be a potential drug for use in anti-epileptogenic therapy.Accumulating data have revealed that abnormal activity of the mTOR(mammalian target of rapamycin)pathway plays an important role in epileptogenesis triggered by various factors. We previously reported that pretreatment with perifosine, an inhibitor of Akt(also called protein kinase B), abolishes the rapamycin-induced paradoxical increase of S6 phosphorylation in a rat model induced by kainic acid(KA). Since Akt is an upstream target in the mTOR signaling pathway, we set out to determine whether perifosine has a preventive effect on epileptogenesis. Here, we explored the effect of perifosine on the model of temporal epilepsy induced by KA in rats and found that pretreatment with perifosine had no effect on the severity or duration of the KA-induced status epilepticus. However, perifosine almost completely inhibited the activation of p-Akt and p-S6 both acutely and chronically following the KA-induced status epilepticus.Perifosine pretreatment suppressed the KA-induced neuronal death and mossy fiber sprouting. The frequency of spontaneous seizures was markedly decreased in rats pretreated with perifosine. Accordingly, rats pretreated with perifosine showed mild impairment in cognitive functions. Collectively, this study provides novel evidence in a KA seizure model that perifosine may be a potential drug for use in anti-epileptogenic therapy.

关 键 词：Akt-mTOR signaling PERIFOSINE Kainic acid Spontaneous seizure Cognitive function 

分 类 号：R-332[医药卫生] R742.1