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

作　　者：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 Xiao-dong Fan Lu Sun Ji-hong Han Xiao-xiao Yang 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2023年第2期308-320,共13页中国药理学报（英文版）

基　　金：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.

摘　　要：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-1αin 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-1αstabilizer,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 20μM)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-1αactivators as therapeutics for migraine.

关 键 词：MIGRAINE HIF-1Α roxadustat central sensitization NEUROINFLAMMATION ROS 

分 类 号：R73[医药卫生—肿瘤]