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7,8-Dihydroxyflavone protects retinal ganglion cells against chronic intermittent hypoxia-induced oxidative stress damage via activation of the BDNF/TrkB signaling pathway

  • Sleep Breathing Physiology and Disorders • Original Article
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Abstract

Purpose

Chronic intermittent hypoxia (CIH) plays a key role in the complications of obstructive sleep apnea (OSA), which is strongly associated with retinal and optic nerve diseases. Additionally, the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathway plays an important protective role in neuronal injury. In the present study, we investigated the role of 7,8-dihydroxyflavone (7,8-DHF) in regulating CIH-induced injury in mice retinas and rat primary retinal ganglion cells (RGCs).

Methods

C57BL/6 mice and in vitro primary RGCs were exposed to CIH or normoxia and treated with or without 7,8-DHF. The mice eyeballs or cultured cells were then taken for histochemistry, immunofluorescence or biochemistry, and the protein expression of the BDNF/TrkB signaling pathway analysis.

Results

Our results showed that CIH induced oxidative stress (OS) in in vivo and in vitro models and inhibited the conversion of BDNF precursor (pro-BDNF) to a mature form of BDNF, which increased neuronal cell apoptosis. 7,8-DHF reduced the production of reactive oxygen species (ROS) caused by CIH and effectively activated TrkB signals and downstream protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) survival signaling pathways, which upregulated the expression of mature BDNF. ANA-12 (a TrkB specific inhibitor) blocked the protective effect of 7,8-DHF.

Conclusion

In short, the activation of the BDNF/TrkB signaling pathway alleviated CIH-induced oxidative stress damage of the optic nerve and retinal ganglion cells. 7,8-DHF may serve as a promising agent for OSA related neuropathy.

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Acknowledgements

We would like to thank Prof. Hong Zhang and Dr. Hong-Li Liu, who specialize in ophthalmology in Tongji Hospital affiliated of Tongji Medical College of Huazhong University of Science and Technology, for their technical assistance.

Funding

This work was supported by the National Natural Science Foundation of China (grant number 81770086) and the National Key Research and Development Program of China (grant number 2016YFC1304203).

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Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China

    Yuan-yuan Fang, Miao Luo, Shuang Yue, Yin Han, Huo-jun Zhang, Yu-hao Zhou, Kui Liu & Hui-guo Liu

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Contributions

Y.-Y.F., M.L., and K.L. conceived and supervised the project. Y.-Y.F., S.Y., Y.H., and Y.-H.Z. conducted the experiments and analyzed the data. Y.-Y.F., M.L., and H.-J.Z. wrote the manuscript. H.-G.L. revised the manuscript and approved the article.

Corresponding author

Correspondence to Hui-guo Liu.

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Ethics approval

All experimental procedures described in the present study were approved by the Institutional Animal Care and Use Committee of Tongji Medical College at Huazhong University of Science and Technology (TJH-201901002) and were performed in accordance with the ARVO statement for the Use of Animals in Ophthalmic and Vision Research and NIH guidelines for the care and use of animals in research.

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The authors declare no competing interests.

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Fang, Yy., Luo, M., Yue, S. et al. 7,8-Dihydroxyflavone protects retinal ganglion cells against chronic intermittent hypoxia-induced oxidative stress damage via activation of the BDNF/TrkB signaling pathway. Sleep Breath 26, 287–295 (2022). https://doi.org/10.1007/s11325-021-02400-5

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