Inhibition of mTOR Signal Reduces Epileptogenesis by Inhibiting Early Inflammatory Responses

Accumulating evidence suggests that brain inflammation is an important mechanism that promotes epileptogenesis and seizure development. This topic was inspired from the tuberous sclerosis (TSC), in the pathogenesis of the deletion of Tsc1/2 gene induced by the mammalian target of rapamycin (mTOR) abnormal activation signal, which is associated with intractable epilepsy. mTOR specific inhibitor can reduce TSC subependymal nodules, and seizures eased. While the mTOR inhibitors are also powerful immunosuppressant, we presumed that mTOR signal abnormal activation was involved in the chronic epileptogenesis after seizures, whether mTOR inhibitors could prevent the epileptogenesis by inhibiting the early inflammatory factors via mTOR signal. We induced seizures in rats (P10d) by intraperitoneal injection kainic acid (KA), and pretreatment of rapamycin was given intraperitoneally (6 mg/kg/day under isoflurane anesthesia) for 3 consecutive days prior to kainate injection, once daily for 7 days. The experiment rats were divided into KA group, KA+RAP group and Control group. We observed the difference of chronic spontaneous seizures (SRS) occurred in the groups. This study will research the alteration of the mTOR signal after seizures in immature rats. We also study the effects of mTOR inhibitors on astrocytes, microglia and early inflammatory factors such as IL-1β, COX-2, TGF- 1 after KA induced-SE. mTOR inhibitors can reduce the occurrence of SRS in chronic phase, and inhibit the gene and protein expression of early inflammatory cytokines of IL-1, TGF-1 and COX-2 level, Which may provide new ideas and methods to prevent the formation of chronic epilepsy.

Author(s): Haiju Zhang, Baozhen Yao, Xiao Zhang, Wei Ling and Hao Yuan

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