PMID- 38373662 OWN - NLM STAT- MEDLINE DCOM- 20240315 LR - 20240315 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 326 DP - 2024 May 23 TI - Amelioration of nitroglycerin-induced migraine in mice via Wuzhuyu decoction: Inhibition of the MZF1/PGK1 pathway and activation of NRF2 antioxidant response. PG - 117930 LID - S0378-8741(24)00229-0 [pii] LID - 10.1016/j.jep.2024.117930 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Migraine, a chronic and intricate disorder, manifests as recurrent episodic headaches accompanied by various neurological symptoms. Wuzhuyu Decoction (WZYD) is a traditional Chinese medical formula with promising effects in treating migraines; however, its underlying mechanisms have not yet been clarified. AIM OF STUDY: The study aimed to evaluate WZYD's effectiveness in migraine treatment and investigate the potential mechanism of WZYD's effects on migraine and oxidative stress. MATERIALS AND METHODS: Behavior tests and immunofluorescence assay for the intensity of migraine markers to assess the migraine-relieving effect of WZYD after chronic migraine model induced by nitroglycerin in mice. The impacts of WZYD on oxidative stress-related markers, including reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase 1 (HO1), and NAD (P)H quinone oxidoreductase 1 (NQO1) in brain tissue were examined. In addition, protein expression or mRNA levels of the MZF1/PGK1 were detected using Western blot or PCR, respectively. Finally, the MZF1 overexpression vector was constructed to the higher level of MZF1. The MZF1/PGK1 signaling pathway expression was evaluated by markers of oxidative stress including NRF2 and others in this series of experiments. RESULTS: Through murine model experimentation, we observed that WZYD effectively alleviates migraine symptoms, signifying its therapeutic efficacy. Mechanistically, WZYD emerges as a potent activator of the NRF2, acting as a robust defense against oxidative stress. In vitro investigations demonstrated that WZYD combats oxidative stress and curbs cell apoptosis induced by these detrimental conditions. Furthermore, by suppressing the transcriptional expression of PGK1, an influential player in the NRF2 pathway, WZYD effectively activates NRF2 signaling. Intriguingly, we have identified MZF1 as the mediator orchestrating the regulation of the PGK1/NRF2 pathway by WZYD. CONCLUSION: The study confirms the effectiveness of WZYD in alleviating migraine symptoms. Mechanistically, WZYD activated the NRF2 signaling pathway; moreover, the action of WZYD involved the down-regulation of PGK1 mediated by MZF1, which promoted the activation of the NRF2 pathway. This study advances our understanding of the intricate mechanisms driving WZYD's efficacy, paving the way for novel treatments in migraine management. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Xu, Min AU - Xu M AD - Department of Neurosurgery, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, 215300, Jiangsu Province, China. Electronic address: xumin7706@163.com. FAU - Zhang, Jiayan AU - Zhang J AD - School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China. Electronic address: zhangjy@njucm.edu.cn. FAU - Shi, Zhenhua AU - Shi Z AD - Department of Neurosurgery, Changshu No.2 People's Hospital, The Affiliated Changshu Hospital of Nantong University, Changshu, 215500, Jiangsu Province, China. Electronic address: shizhenhua1309@163.com. FAU - He, Ziyang AU - He Z AD - Department of Neurosurgery, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, 215300, Jiangsu Province, China. Electronic address: frank19950727@163.com. FAU - Zhao, Yijing AU - Zhao Y AD - School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China. Electronic address: zhaoyijing@njucm.edu.cn. FAU - Ling, Xiaoyang AU - Ling X AD - Department of Neurosurgery, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, 215300, Jiangsu Province, China. Electronic address: lingyang0188@163.com. FAU - Wang, Wenhua AU - Wang W AD - Department of Neurosurgery, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, 215300, Jiangsu Province, China. Electronic address: 13776118488@163.com. FAU - Gong, Mingjie AU - Gong M AD - Department of Neurosurgery, Changshu No.2 People's Hospital, The Affiliated Changshu Hospital of Nantong University, Changshu, 215500, Jiangsu Province, China. Electronic address: gmjapple@126.com. LA - eng PT - Journal Article DEP - 20240217 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Antioxidants) RN - 0 (NF-E2-Related Factor 2) RN - G59M7S0WS3 (Nitroglycerin) RN - 0 (Reactive Oxygen Species) SB - IM MH - Mice MH - Animals MH - *Antioxidants/pharmacology/therapeutic use/metabolism MH - NF-E2-Related Factor 2/genetics/metabolism MH - Nitroglycerin MH - Antioxidant Response Elements MH - Oxidative Stress MH - Reactive Oxygen Species/metabolism MH - *Migraine Disorders/chemically induced/drug therapy/genetics OTO - NOTNLM OT - MZF1 OT - Migraine OT - NRF2 OT - PGK1 OT - Wuzhuyu decoction COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/02/20 11:50 MHDA- 2024/03/15 06:44 CRDT- 2024/02/19 19:17 PHST- 2023/12/15 00:00 [received] PHST- 2024/02/11 00:00 [revised] PHST- 2024/02/16 00:00 [accepted] PHST- 2024/03/15 06:44 [medline] PHST- 2024/02/20 11:50 [pubmed] PHST- 2024/02/19 19:17 [entrez] AID - S0378-8741(24)00229-0 [pii] AID - 10.1016/j.jep.2024.117930 [doi] PST - ppublish SO - J Ethnopharmacol. 2024 May 23;326:117930. doi: 10.1016/j.jep.2024.117930. Epub 2024 Feb 17.