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.

中枢疼痛和炎症通路的敏感性在偏头痛（一种原发性神经生物学头痛疾病）中起着重要作用。由于缺氧诱导因子 1α (HIF-1α) 与神经保护和炎症抑制有关，因此我们在此研究了 HIF-1α 在偏头痛中的作用。通过每隔一天重复注射硝酸甘油 (10 mg/kg, ip)，总共注射 5 次，在小鼠中建立慢性偏头痛模型。在预防和急性实验中，roxadustat 是一种 HIF-1α 稳定剂，分别在硝酸甘油注射之前或之后开始口服给药。进行了压力应用测量、甩尾和厌光行为测试，以确定压力痛阈值、热伤害敏感度和偏头痛相关的光敏感度。在实验结束时，收集小鼠血清样本和脑组织用于分析。我们表明，罗沙司他给药可通过改善中枢致敏作用显着减轻硝酸甘油诱导的基础超敏反应和急性痛觉过敏。Roxadustat 给药还通过 NF-κB 通路降低了血清和三叉神经尾核 (TNC) 中的炎性细胞因子水平。与表明罗沙司他抑制小胶质细胞活化的体内结果一致，罗沙司他（2、10 和 20 μM）通过抑制 HIF- 1α/NF-κB通路。综上所述，这项研究表明，罗沙司他给药可改善注射硝酸甘油的小鼠的偏头痛样行为并抑制中枢痛敏化，