{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:45:12Z","timestamp":1787496312922,"version":"build-2736575974"},"reference-count":62,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008836","name":"Gaziantep University","doi-asserted-by":"publisher","award":["1"],"award-info":[{"award-number":["1"]}],"id":[{"id":"10.13039\/501100008836","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Migraine is the most common primary headache disorder worldwide, negatively affecting quality of life and limiting the functionality of individuals. Although its pathogenesis is not fully understood, it is known that activation of the trigeminovascular system, neurogenic inflammation, and oxidative stress are among the main components of migraine. In this context, we aimed to investigate the possible role of the nuclear factor erythroid 2-related factor 2 (Nrf2)\/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway, which plays a key role in the regulation of cellular oxidative stress, in the development of chronic diseases such as migraine. Materials and Methods: In this study, the oxidative stress parameters total oxidant level (TOS), total antioxidant level (TAS), and oxidative stress index (OSI) and changes in the Nrf2\/Keap1 signaling pathway were analyzed in migraine patients. Results: The results showed that Keap1 levels were significantly higher in migraine patients compared with the control group, whereas the Nrf2 and TAS levels were low. In addition, increased levels of oxidized LDL (oxLDL) and glycogen synthase kinase-3 beta (GSK3B), which are oxidative stress markers, confirmed that the oxidative stress burden was high in migraine patients. The fact that OSI values were significantly higher in migraine patients clearly demonstrates that systemic oxidative stress was out of balance in these individuals. Conclusions: In conclusion, this study reveals that oxidative stress and the Nrf2\/Keap1 signaling pathway play an important role in the pathogenesis of migraine. Decreased Nrf2 activity and increased Keap1 levels suggest that the antioxidant defense system is insufficient in migraine patients. These findings suggest that the Nrf2\/Keap1 signaling pathway may be considered as a potential target for migraine treatment and that the development of new treatment strategies to reduce oxidative stress may be beneficial.<\/jats:p>","DOI":"10.3390\/medicina61101732","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T08:19:45Z","timestamp":1758701985000},"page":"1732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evaluation of Nrf2\/Keap1 Pathway in Patients with Migraine"],"prefix":"10.3390","volume":"61","author":[{"given":"Fatih","family":"Ko\u00e7t\u00fcrk","sequence":"first","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, 46040 Kahramanmaras, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firdevs","family":"Emekli","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Gaziantep University, 27310 Gaziantep, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4802-0994","authenticated-orcid":false,"given":"Kadir","family":"E\u011fi","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Gaziantep University, 27310 Gaziantep, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1251-3148","authenticated-orcid":false,"given":"Seyithan","family":"Taysi","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Gaziantep University, 27310 Gaziantep, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41582-021-00509-5","article-title":"Diagnosis and management of migraine in ten steps","volume":"17","author":"Eigenbrodt","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1056\/NEJMra1915327","article-title":"Migraine","volume":"383","author":"Migraine","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1474-4422(18)30499-X","article-title":"Global, regional, and national burden of neurological disorders, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Feigin","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/S1474-4422(18)30322-3","article-title":"Global, regional, and national burden of migraine and tension-type headache, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"17","author":"Stovner","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e067670","DOI":"10.1136\/bmj-2021-067670","article-title":"Management of chronic migraine","volume":"379","author":"Hovaguimian","year":"2022","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/0333102417738202","article-title":"Headache classification committee of the international headache society (IHS) the international classification of headache disorders","volume":"38","author":"Arnold","year":"2018","journal-title":"Cephalalgia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"P130","DOI":"10.1186\/1129-2377-14-S1-P130","article-title":"Migraine headache is present in the aura phase\u2013a prospective study","volume":"14","author":"Hansen","year":"2013","journal-title":"J. Headache Pain."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/j.1468-2982.2009.01941.x","article-title":"Global prevalence of chronic migraine: A systematic review","volume":"30","author":"Natoli","year":"2010","journal-title":"Cephalalgia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"g1416","DOI":"10.1136\/bmj.g1416","article-title":"Chronic migraine","volume":"348","author":"Schwedt","year":"2014","journal-title":"BMJ"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(19)30185-1","article-title":"Migraine and the trigeminovascular system\u201440 years and counting","volume":"18","author":"Ashina","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1016\/S0140-6736(20)32342-4","article-title":"Migraine: Integrated approaches to clinical management and emerging treatments","volume":"397","author":"Ashina","year":"2021","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1152\/physrev.00034.2015","article-title":"Pathophysiology of migraine: A disorder of sensory processing","volume":"97","author":"Goadsby","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/head.14120","article-title":"Patient-identified most bothersome symptom in preventive migraine treatment with eptinezumab: A novel patient-centered outcome","volume":"61","author":"Lipton","year":"2021","journal-title":"Headache J. Head Face Pain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s10194-016-0599-8","article-title":"Interictal burden attributable to episodic headache: Findings from the Eurolight project","volume":"17","author":"Lampl","year":"2016","journal-title":"J. Headache Pain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/head.13300","article-title":"A phase-by-phase review of migraine pathophysiology","volume":"58","author":"Dodick","year":"2018","journal-title":"Headache J. Head Face Pain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s41582-018-0098-4","article-title":"Biological insights from the premonitory symptoms of migraine","volume":"14","author":"Karsan","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1097\/WCO.0b013e32836085f4","article-title":"Migraine: A brain state","volume":"26","author":"Charles","year":"2013","journal-title":"Curr. Opin. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1093\/brain\/awt320","article-title":"Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks","volume":"137","author":"Maniyar","year":"2014","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6619","DOI":"10.1523\/JNEUROSCI.0373-15.2015","article-title":"Migraine: Multiple processes, complex pathophysiology","volume":"35","author":"Burstein","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1093\/brain\/aww097","article-title":"The migraine generator revisited: Continuous scanning of the migraine cycle over 30 days and three spontaneous attacks","volume":"139","author":"Schulte","year":"2016","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1177\/0333102417698953","article-title":"Chronotypes and circadian timing in migraine","volume":"38","author":"Schoonman","year":"2018","journal-title":"Cephalalgia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1007\/s00415-023-11706-1","article-title":"Migraine: From pathophysiology to treatment","volume":"270","author":"Puledda","year":"2023","journal-title":"J. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/nrn3057","article-title":"Diencephalic and brainstem mechanisms in migraine","volume":"12","author":"Akerman","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.ncl.2019.07.008","article-title":"An Update: Pathophysiology of Migraine","volume":"37","author":"Goadsby","year":"2019","journal-title":"Neurol. Clin."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrneurol.2010.127","article-title":"CGRP and its receptors provide new insights into migraine pathophysiology","volume":"6","author":"Ho","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/head.13529","article-title":"CGRP and the trigeminal system in migraine","volume":"59","author":"Iyengar","year":"2019","journal-title":"Headache J. Head Face Pain."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1002\/acn3.113","article-title":"Pituitary adenylate cyclase activating polypeptide and migraine","volume":"1","author":"Zagami","year":"2014","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1093\/brain\/awt369","article-title":"Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38","volume":"137","author":"Amin","year":"2014","journal-title":"Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"82","DOI":"10.2302\/kjm.60.82","article-title":"Neuropeptide effects in the trigeminal system: Pathophysiology and clinical relevance in migraine","volume":"60","author":"Messlinger","year":"2011","journal-title":"Keio J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Moulton, E.A., Becerra, L., Johnson, A., Burstein, R., and Borsook, D. (2014). Altered hypothalamic functional connectivity with autonomic circuits and the locus coeruleus in migraine. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095508"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1136\/jnnp.2008.157743","article-title":"Cranial autonomic symptoms in migraine: Characteristics and comparison with cluster headache","volume":"80","author":"Lai","year":"2009","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/14737175.2018.1414601","article-title":"Dysautonomia in the pathogenesis of migraine","volume":"18","author":"Gazerani","year":"2018","journal-title":"Expert Rev. Neurother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/cne.20688","article-title":"Unitary hypothesis for multiple triggers of the pain and strain of migraine","volume":"493","author":"Burstein","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1177\/0333102416636097","article-title":"Can migraine aura be provoked experimentally? A systematic review of potential methods for the provocation of migraine aura","volume":"37","author":"Lindblad","year":"2017","journal-title":"Cephalalgia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1212\/WNL.0b013e31827f0f10","article-title":"Provocation of migraine with aura using natural trigger factors","volume":"80","author":"Hougaard","year":"2013","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8344","DOI":"10.1007\/s12035-024-04114-7","article-title":"Oxidative Stress and Migraine","volume":"61","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"50708","DOI":"10.18632\/oncotarget.9367","article-title":"Molecular factors in migraine","volume":"7","author":"Kowalska","year":"2016","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Mart\u00edn, E., Navarro-Mu\u00f1oz, S., Ayuso, P., Rodr\u00edguez, C., Serrador, M., Alonso-Navarro, H., Calleja, M., Navacerrada, F., Turp\u00edn-Fenoll, L., and Recio-Bermejo, M. (2023). Lack of association between common LAG3\/CD4 variants and risk of migraine. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021292"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13561","DOI":"10.1073\/pnas.1121572109","article-title":"Keap1 degradation by autophagy for the maintenance of redox homeostasis","volume":"109","author":"Taguchi","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.freeradbiomed.2015.06.006","article-title":"Molecular basis of the Keap1\u2013Nrf2 system","volume":"88","author":"Suzuki","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Liddell, J.R. (2017). Are astrocytes the predominant cell type for activation of Nrf2 in aging and neurodegeneration?. Antioxidants, 6.","DOI":"10.3390\/antiox6030065"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s10194-016-0606-0","article-title":"Oxidative stress and DNA damage in patients with migraine","volume":"17","author":"Geyik","year":"2016","journal-title":"J. Headache Pain"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.clinbiochem.2003.10.014","article-title":"A novel automated method to measure total antioxidant response against potent free radical reactions","volume":"37","author":"Erel","year":"2004","journal-title":"Clin. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.clinbiochem.2005.08.008","article-title":"A new automated colorimetric method for measuring total oxidant status","volume":"38","author":"Erel","year":"2005","journal-title":"Clin. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zobdeh, F., Eremenko, I.I., Akan, M.A., Tarasov, V.V., Chubarev, V.N., Schi\u00f6th, H.B., and Mwinyi, J. (2023). The epigenetics of migraine. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119127"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"105490","DOI":"10.1016\/j.neuint.2023.105490","article-title":"Oxidative stress, inflammation and hormesis: The role of dietary and lifestyle modifications on aging","volume":"164","author":"Sharma","year":"2023","journal-title":"Neurochem. Int."},{"key":"ref_47","first-page":"45","article-title":"The effects of phytosomal curcumin supplementation on clinical symptoms, and inflammatory and oxidative stress biomarkers in patients with migraine: A protocol for a randomized double-blind placebo-controlled trial","volume":"13","author":"Shojaei","year":"2023","journal-title":"Avicenna J. Phytomed."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S1474-4422(09)70358-8","article-title":"Migraine aura pathophysiology: The role of blood vessels and microembolisation","volume":"9","author":"Dalkara","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/head.12725","article-title":"Migraine triggers and oxidative stress: A narrative review and synthesis","volume":"56","author":"Borkum","year":"2016","journal-title":"Headache: J. Head Face Pain"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","article-title":"Role of nrf2 in oxidative stress and toxicity","volume":"53","author":"Ma","year":"2013","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/j.1468-1331.2009.02865.x","article-title":"Migraine, lipid profile, and cardiovascular disease","volume":"17","author":"Bigal","year":"2009","journal-title":"Eur. J. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1111\/j.1468-1331.2009.02861.x","article-title":"Lipid profile in normal weight migraineurs\u2013evidence for cardiovascular risk","volume":"17","author":"Gruber","year":"2010","journal-title":"Eur. J. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1212\/01.WNL.0000151857.43225.49","article-title":"Cardiovascular risk factors and migraine: The GEM population-based study","volume":"64","author":"Scher","year":"2005","journal-title":"Neurology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1038\/onc.2014.390","article-title":"Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cell growth","volume":"34","author":"Elya","year":"2015","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2011.03.005","article-title":"GSK3: A key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease","volume":"23","author":"Gao","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1007\/s11596-013-1154-3","article-title":"Role of GSK-3\u03b2 in isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats","volume":"33","author":"Li","year":"2013","journal-title":"J. Huazhong Univ. Sci. Technol. [Med. Sci.]"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"189246","DOI":"10.4061\/2011\/189246","article-title":"GSK-3 in neurodegenerative diseases","volume":"2011","author":"Lei","year":"2011","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.phrs.2015.03.010","article-title":"Glycogen synthase kinase-3 beta (GSK-3\u03b2) signaling: Implications for Parkinson\u2019s disease","volume":"97","author":"Golpich","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Chen, S.-D., Yang, J.-L., Lin, T.-K., and Yang, D.-I. (2019). Emerging roles of sestrins in neurodegenerative diseases: Counteracting oxidative stress and beyond. J. Clin. Med., 8.","DOI":"10.3390\/jcm8071001"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1159\/000484060","article-title":"Recent insights into the biological functions of sestrins in health and disease","volume":"43","author":"Wang","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1002\/emmm.201000097","article-title":"Stressin\u2019 Sestrins take an aging fight","volume":"2","author":"Budanov","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.tibs.2016.04.005","article-title":"Biochemical basis of sestrin physiological activities","volume":"41","author":"Ho","year":"2016","journal-title":"Trends Biochem. Sci."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/61\/10\/1732\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:48:37Z","timestamp":1760035717000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/61\/10\/1732"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,24]]},"references-count":62,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["medicina61101732"],"URL":"https:\/\/doi.org\/10.3390\/medicina61101732","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,24]]}}}