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Roxadustat alleviates nitroglycerin-induced migraine in mice by regulating HIF-1α/NF-κB/inflammation pathway

Acta Pharmacologica Sinica volume 44, pages 308–320 (2023)Cite this article

Abstract

Sensitization of central pain and inflammatory pathways play essential roles in migraine, a primary neurobiological headache disorder. Since hypoxia-inducible factor-1α (HIF-1α) is implicated in neuroprotection and inflammation inhibition, herein we investigated the role of HIF-1α in migraine. A chronic migraine model was established in mice by repeated injection of nitroglycerin (10 mg/kg, i.p.) every other day for 5 total injections. In the prevention and acute experiments, roxadustat, a HIF-1α stabilizer, was orally administered starting before or after nitroglycerin injection, respectively. Pressure application measurement, and tail flick and light-aversive behaviour tests were performed to determine the pressure pain threshold, thermal nociceptive sensitivity and migraine-related light sensitivity. At the end of experiments, mouse serum samples and brain tissues were collected for analyses. We showed that roxadustat administration significantly attenuated nitroglycerin-induced basal hypersensitivity and acute hyperalgesia by improving central sensitization. Roxadustat administration also decreased inflammatory cytokine levels in serum and trigeminal nucleus caudalis (TNC) through NF-κB pathway. Consistent with the in vivo results showing that roxadustat inhibited microglia activation, roxadustat (2, 10, and 20 μM) dose-dependently reduced ROS generation and inflammation in LPS-stimulated BV-2 cells, a mouse microglia cell line, by inhibiting HIF-1α/NF-κB pathway. Taken together, this study demonstrates that roxadustat administration ameliorates migraine-like behaviours and inhibits central pain sensitization in nitroglycerin-injected mice, which is mainly mediated by HIF-1α/NF-κB/inflammation pathway, suggesting the potential of HIF-1α activators as therapeutics for migraine.

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Fig. 1: Roxadustat reduces LPS-induced intracellular ROS levels in BV-2 cells.
Fig. 2: Roxadustat protects against LPS-induced inflammation in BV-2 cells.
Fig. 3: Preventative treatment with roxadustat improves NTG-induced migraine in C57BL/6J mice.
Fig. 4: Preventative treatment with roxadustat ameliorates NTG-induced neuroinflammation.
Fig. 5: Acute treatment with roxadustat improves NTG-induced migraine in C57BL/6 J mice.
Fig. 6: Acute treatment with roxadustat improves NTG-induced central sensitization in TNC.
Fig. 7: Acute treatment with roxadustat ameliorates NTG-induced neuroinflammation and systemic inflammation.
Fig. 8: Schematic diagram for the role of roxadustat in NTG-induced migraine.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) Grants 81973316 to JHH, 82173807 to YJD; Tianjin Municipal Science and Technology Commission of China Grant 20JCZDJC00710 and the Fundamental Research Funds for the Central Universities (Nankai University) 63211045 to HJH; the Fund from Tianjin Municipal Health Commission Grant ZC200093 the Open Fund of Tianjin Central Hospital of Gynecology Obstetrics/Tianjin Key Laboratory of human development and reproductive regulation to XDF.

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  1. These authors contributed equally: Dai-gang Yang, Yong-yao Gao

Authors and Affiliations

  1. Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China

    Dai-gang Yang, Yong-yao Gao, Ze-qun Yin, Xue-rui Wang, Xian-she Meng, Ting-feng Zou, Ya-jun Duan, Yuan-li Chen, Chen-zhong Liao, Zhou-ling Xie, Ji-hong Han & Xiao-xiao Yang

  2. Department of General Gynecology, Tianjin Central Hospital of Gynecology and Obstetrics/Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, 300100, China

    Xiao-dong Fan & Lu Sun

  3. College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, 300071, China

    Ji-hong Han

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Contributions

XXY and JHH conceived and designed the study. DGY and YYG, ZQY, XRW, XSM, and TFZ, performed, analyzed, and interpreted studies data. DGY and XXY wrote the paper. XXY, JHH, YJD, YLC, CZL, ZLX, LS and XDF contributed reagents/materials/analysis tools and revised the paper. All authors discussed the data and commented on the manuscript.

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Correspondence to Ji-hong Han or Xiao-xiao Yang.

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Yang, Dg., Gao, Yy., Yin, Zq. et al. Roxadustat alleviates nitroglycerin-induced migraine in mice by regulating HIF-1α/NF-κB/inflammation pathway. Acta Pharmacol Sin 44, 308–320 (2023). https://doi.org/10.1038/s41401-022-00941-3

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Keywords

  • migraine
  • HIF-1α
  • roxadustat
  • central sensitization
  • neuroinflammation
  • ROS

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