mTOR/NF-κB signaling pathway protects hippocampal neurons from injury induced by intermittent hypoxia in rats

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.

Keywords:

• Hippocampal neurons
• intermittent hypoxia
• NF-kB/mTOR signaling pathway
• Rapa
• PDTC
• obstructive sleep apnea

Disclosure statement

The authors declare that they have no conflict of interest.

Authors’ contributions

Concept and design: CQZ, YZL, SY; Analysis and interpretation of the data: CQZ, SY, PPC; Draft of the article: BBC, YW, YZL; Critical revision and final approval of the article: CQZ, SY, PPC, BBC, YW, YZL; Statistical expertise: SY; acquisition of data: CQZ, PPC, SY; CQZ and SY contributed equally to this research.

Additional information

Funding

This work was supported by National Natural Science Foundation of China (NO. 81170903) and Natural Science Foundation of Shandong Province (NO. ZR2018MH017). The sponsor had no role in the design or conduct of this research.