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

Dai-gang Yang1, Yong-yao Gao1, Ze-qun Yin1, Xue-rui Wang1, Xian-she Meng1, Ting-feng Zou1, Ya-jun Duan1, Yuan-li Chen1, Chen-zhong Liao1, Zhou-ling Xie1, Xiao-dong Fan2, Lu Sun2, Ji-hong Han1,3, Xiao-xiao Yang1
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
2 Department of General Gynecology, Tianjin Central Hospital of Gynecology and Obstetrics/Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin 300100, China
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
Correspondence to: Ji-hong Han:, Xiao-xiao Yang:,
DOI: 10.1038/s41401-022-00941-3
Received: 31 December 2021
Accepted: 8 June 2022
Advance online: 10 August 2022


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.
Keywords: migraine; HIF-1α; roxadustat; central sensitization; neuroinflammation; ROS

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