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

Abstract

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.

Is Mossy Fiber Sprouting a Potential Therapeutic Target for Epilepsy?

“…Another Akt inhibitor called perifosine, was used prior to SE induced by kainic acid (KA). Pretreatment with perifosine suppressed the KA-induced neuronal death and MFS, resulting in a decrease in spontaneous seizures ( 129 ). These data support the hypothesis that MFS, after the epileptogenesis process, may lead to, but it is not necessary for the formation of recurrent excitatory circuits in dentate granule cells.…”

“…A list of a few relevant studies with different subjects, models and treatments for MTLE is listed in Table 1 . In this table we listed studies that had success in suppressing both the MFS and spontaneous seizures ( 184 , 186 , 189 ); suppressed MFS but had no effect on spontaneous seizures ( 101 , 109 , 129 , 143 , 144 , 187 , 188 ) or suppressed seizures but had no effect on MFS ( 183 ). Among these studies, systemically infused mesenchymal stem cells (MSCs) suppressed aberrant MFS in the hippocampus in the lithium-pilocarpine injection model ( 184 ).…”

Fangjing decoction relieves febrile seizures-induced hippocampal neuron apoptosis in rats via regulating the Akt/mTOR pathway

“…It is generally known that protein kinase B (Akt) plays a critical role in the manipulation of diverse cellular functions, such as metabolism, proliferation, survival, transcription, and protein synthesis [ 4 ]. The mammalian target of rapamycin (mTOR) is another serine/threonine kinase that controls protein synthesis related to cell growth and proliferation [ 5 ].…”

Anterior thalamic nuclei deep brain stimulation inhibits mossy fiber sprouting via 3′,5′-cyclic adenosine monophosphate/protein kinase A signaling pathway in a chronic epileptic monkey model

“…Pre-treatment with perifosine, an inhibitor of Akt, suppressed KA-induced neuronal death and MFS. [ 31 ] The frequency of spontaneous seizures was also markedly reduced in rats pre-treated with perifosine. [ 31 ] Mycophenolate mofetil, which is commonly used as an immunosuppressant in organ transplantations, reduces MFS in the DG and CA3 regions of the hippocampus, possibly via the Akt signaling pathway.…”