Abstract

Objective

To expound the roles of mTOR and NF-kB signaling pathway in intermittent hypoxia (IH)-induced damage of hippocampal neurons.

Methods

For rat experiments, mTOR inhibitor (Rapamycin, Rapa) and NF-κB signaling inhibitor (ammonium pyrrolidine dithiocarbamate, PDTC) were applied to inhibit mTOR and NF-κB signaling, respectively. For neuron experiments, hippocampal neurons from rat were successfully cultured. Different concentrations of Rapa and PDTC were added to the cultured hippocampal neurons. Rat or primary hippocampal neurons were exposed to normoxic or IH conditions after administration of Rapa and PDTC. The effects of Rapa and PDTC administration on learning and memory ability of rats and hippocampal injury after IH exposure were assayed by Morris water maze and H&E staining. Electron microscope was utilized to examine primary hippocampal neuron ultrastructure changes after IH exposure and Rapa or PDTC administration. The expressions of NF-κB-p65, IκBα, IKKβ, BDNF, TNF-α, IL-1β, PSD-95 and SYN in hippocampal neurons were examined.

Results

Compared with normal control rats or neurons, IH-treated group had elevated expression levels of NF-kB, TNF-α and IL-1β and suppressed expression level of BDNF, PSD-95 and SYN. These results were reversed upon pre-treatment with Rapa and PDTC. Furthermore, IκBα and IKKβ expressions were down-regulated in IH group. No notable difference was manifested in PDTC pre-treatment group, while a prominent increase was shown after Rapa pre-administration.

Conclusion

The administration of PDTC and Rapa could prevent IH-induced hippocampal neuron impairment, indicating that inhibition of the mTOR and NF-κB pathway may likely act as a therapeutic target for obstructive sleep apnea.

中文翻译：

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mTOR/NF-κB信号通路保护大鼠海马神经元免受间歇性缺氧损伤

摘要

客观的

阐述mTOR和NF-kB信号通路在间歇性缺氧(IH)诱导的海马神经元损伤中的作用。

方法

对于大鼠实验，mTOR 抑制剂（雷帕霉素，Rapa）和 NF-κB 信号抑制剂（吡咯烷二硫代氨基甲酸铵，PDTC）分别用于抑制 mTOR 和 NF-κB 信号。对于神经元实验，成功培养了大鼠的海马神经元。将不同浓度的 Rapa 和 PDTC 添加到培养的海马神经元中。大鼠或原代海马神经元在给予 Rapa 和 PDTC 后暴露于常氧或 IH 条件。采用Morris水迷宫和H&E染色法检测Rapa和PDTC给药对大鼠学习记忆能力和IH暴露后海马损伤的影响。电子显微镜用于检查 IH 暴露和 Rapa 或 PDTC 给药后原发性海马神经元超微结构的变化。NF-κB-p65、IκBα、IKKβ、BDNF、TNF-α、

结果

与正常对照组大鼠或神经元相比，IH处理组NF-kB、TNF-α和IL-1β表达水平升高，BDNF、PSD-95和SYN表达水平受到抑制。这些结果在用 Rapa 和 PDTC 预处理后被逆转。此外，IH 组中 IκBα 和 IKKβ 表达下调。PDTC预治疗组无显着差异，而Rapa预给药后显着增加。

结论

PDTC 和 Rapa 的给药可以预防 IH 诱导的海马神经元损伤，表明 mTOR 和 NF-κB 通路的抑制可能作为阻塞性睡眠呼吸暂停的治疗靶点。