{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:52:23Z","timestamp":1791309143621,"version":"4.3.1"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81873256"],"award-info":[{"award-number":["81873256"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Synapse"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>To investigate the protective effects of ligustrazine (Lig) against nitroglycerin (NTG)\u2010induced migraine and explore its underlying mechanisms, with a particular focus on mitochondrial energy metabolism and the coordinated regulation of protease\u2010activated receptor 2 (PAR2), cyclophilin D (CypD), and adenine nucleotide translocator (ANT). An NTG\u2010induced rat migraine model and NTG\u2010challenged PC12 cells were utilized. Migraine\u2010like behaviors, cell viability, oxidative stress, and mitochondrial function parameters (reactive oxygen species [ROS], nitric oxide [NO], mitochondrial membrane potential [MMP], ATP, and lactic acid) were evaluated. The expression of PAR2, CypD, and ANT was analyzed via Western blotting. Erastin was applied to verify the specific mechanisms. Furthermore, immunoprecipitation\u2010mass spectrometry (IP\u2010MS) was performed to identify CypD\u2010interacting proteins. Validating IP\u2010MS results through protein docking. Lig significantly alleviated NTG\u2010induced migraine\u2010like behaviors in rats and improved the viability of NTG\u2010challenged PC12 cells. Biochemically, Lig mitigated oxidative stress and mitochondrial dysfunction by reducing ROS, NO, and lactic acid levels while restoring MMP and ATP production. Mechanistically, Lig effectively suppressed the NTG\u2010induced upregulation of PAR2, CypD, and ANT. The application of Erastin abolished Lig's protective efficacy, confirming its dependence on mitochondrial energy metabolism pathways. Additionally, IP\u2010MS successfully identified 46 CypD\u2010interacting proteins, expanding the mechanistic understanding of migraine pathogenesis. The protein docking results also support the reliability of the IP\u2010MS results. Lig effectively alleviates NTG\u2010induced migraine by restoring mitochondrial energy metabolism, in close association with the coordinated modulation of PAR2, CypD, and ANT expression. These findings highlight Lig as a promising therapeutic candidate and offer potential molecular targets for clinical migraine management.<\/jats:p>","DOI":"10.1002\/syn.70062","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:15:01Z","timestamp":1791306901000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ligustrazine Alleviates Nitroglycerin\u2010Induced Migraine by Regulating Mitochondrial Energy Metabolism Through the Concurrent Regulation of CypD, ANT, and PAR2"],"prefix":"10.1002","volume":"80","author":[{"given":"Yicheng","family":"Wang","sequence":"first","affiliation":[{"name":"The Affiliated Traditional Chinese Medicine Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangye","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Wu","sequence":"additional","affiliation":[{"name":"The Affiliated Traditional Chinese Medicine Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuxin","family":"Yu","sequence":"additional","affiliation":[{"name":"Clinical College of Integrative Chinese and Western Medicine Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlin","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical College of Integrative Chinese and Western Medicine Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limei","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Mental Health Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changchi","family":"Hu","sequence":"additional","affiliation":[{"name":"Clinical College of Integrative Chinese and Western Medicine Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonglie","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology The Third Affiliated Hospital of Beijing University of Chinese Medicine  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"crossref","DOI":"10.3389\/fneur.2021.800605","article-title":"Migraine: A Review on Its History, Global Epidemiology, Risk Factors, and Comorbidities","volume":"12","author":"Amiri P.","year":"2021","journal-title":"Frontiers In Neurology"},{"issue":"6","key":"e_1_2_15_3_1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/iub.441","article-title":"Protease\u2010Activated Receptors and Myocardial Infarction","volume":"63","author":"Antoniak S.","year":"2011","journal-title":"IUBMB Life"},{"issue":"7033","key":"e_1_2_15_4_1","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/nature03434","article-title":"Loss of Cyclophilin D Reveals a Critical Role for Mitochondrial Permeability Transition in Cell Death","volume":"434","author":"Baines C. 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