Background

Epilepsy is a common chronic neurological disease caused by the over-synchronization of neurons leading to brain dysfunction. Recurrent seizures can lead to cognitive and behavioral deficits, and irreversible brain damage. While the PI3K/Akt/mTOR pathway regulates various physiological processes of neurons and glia, it may also lead to abnormal neuronal signal transduction under pathological conditions, including that of epilepsy. Everolimus (Eve), an mTOR inhibitor, may modulate neuronal excitability and therefore exert protection against epilepsy. Therefore, this study aimed to investigate the neuroprotective effect of Everolimus on seizure-induced brain injury and its regulation of the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway. Kainic acid (KA) 15 mg/kg was used to induce seizures and Everolimus (1, 2, 5 mg/kg) was administered as a pretreatment. Hippocampal tissue was extracted 24 h post-seizure.

Results

The protein and mRNA expression levels of PI3K、p-AKt、p-mTOR、NF-kB and IL-6 as well as neuronal apoptosis and microglia activation, significantly increased after KA-induced seizures, however, these effects were inhibited by Everolimus treatment. Furthermore, pretreatment with Everolimus decreased seizure scores and increased seizure latency.

Conclusions

Everolimus can decrease the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway, reduce neuronal apoptosis and microglia activation, and attenuate seizure susceptibility and intensity, thus having a protective effect on seizure-induced brain damage.

中文翻译：

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依维莫司抑制 PI3K/Akt/mTOR 和 NF-kB/IL-6 信号传导并保护大鼠癫痫发作引起的脑损伤

背景

癫痫是一种常见的慢性神经系统疾病，由神经元过度同步导致脑功能障碍引起。反复发作可导致认知和行为缺陷，以及不可逆转的脑损伤。虽然 PI3K/Akt/mTOR 通路调节神经元和神经胶质细胞的各种生理过程，但它也可能导致在包括癫痫在内的病理条件下神经元信号转导异常。依维莫司 (Eve) 是一种 mTOR 抑制剂，可调节神经元的兴奋性，从而发挥预防癫痫的作用。因此，本研究旨在探讨依维莫司对癫痫性脑损伤的神经保护作用及其对PI3K/Akt/mTOR和NF-kB/IL-6信号通路的调节作用。海藻酸 (KA) 15 mg/kg 用于诱发癫痫发作和依维莫司 (1, 2, 5mg/kg)作为预处理给药。癫痫发作后 24 小时提取海马组织。

结果

KA 诱导的癫痫发作后 PI3K、p-AKt、p-mTOR、NF-kB 和 IL-6 的蛋白和 mRNA 表达水平以及神经元凋亡和小胶质细胞活化显着增加，但依维莫司治疗抑制了这些影响. 此外，依维莫司预处理降低了癫痫发作评分并增加了癫痫发作潜伏期。

结论

依维莫司可降低 PI3K/Akt/mTOR 和 NF-kB/IL-6 信号通路，减少神经元凋亡和小胶质细胞活化，减弱癫痫发作的易感性和强度，从而对癫痫发作引起的脑损伤具有保护作用。