{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T04:27:20Z","timestamp":1787372840435,"version":"build-2736575974"},"reference-count":25,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Social Science Fund of China","award":["25ATY008"],"award-info":[{"award-number":["25ATY008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Currently, effective disease-modifying treatments for Parkinson\u2019s disease (PD) remain lacking. Although exercise has been confirmed to exert neuroprotective effects against PD, its specific molecular mechanisms remain unclear. In particular, the causal role of the Nuclear Factor E2-related Factor 2 (Nrf2)\u2013antioxidant response element (ARE) signaling axis in this process has not been clearly elucidated. This study aimed to provide direct causal evidence that regular treadmill exercise protects the substantia nigra pars compacta (SNc)\u2013striatal dopaminergic system by activating the Nrf2-ARE pathway. The results showed that exercise significantly improved motor function deficits in PD mice, preserved the number of TH-positive neurons, and restored striatal dopamine homeostasis. Mechanistically, exercise activated the Nrf2-ARE pathway, thereby inhibiting the accumulation of mitochondrial ROS (mtROS) and the activation of pro-inflammatory amoeboid microglia in the substantia nigra. Crucially, the improvements in behavioral, neuropathological, and neurochemical indicators induced by exercise were completely reversed, returning to levels comparable to those in the sedentary model group. In conclusion, this study provides clear pharmacological evidence that the neuroprotective effect of regular treadmill exercise against chronic PD strictly depends on the Nrf2-ARE pathway. These findings indicate that Nrf2 is a key mechanistic node linking exercise and neuroprotection, providing reliable preclinical evidence for Nrf2-targeted disease-modifying strategies in PD rehabilitation.<\/jats:p>","DOI":"10.3390\/ijms27167439","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T08:10:20Z","timestamp":1787213420000},"page":"7439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of the Nrf2-ARE Signaling Pathway Mediates the Neuroprotective Effects of Exercise in a Mouse Model of Chronic Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Shuwei","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Physical Education, Hunan Normal University, 529 Lu Shan Nan Road, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4874-1697","authenticated-orcid":false,"given":"Dong","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Physical Education, Hunan Normal University, 529 Lu Shan Nan Road, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changfa","family":"Tang","sequence":"additional","affiliation":[{"name":"College of Physical Education, Hunan Normal University, 529 Lu Shan Nan Road, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Physical Education, Hunan Normal University, 529 Lu Shan Nan Road, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1159\/000505750","article-title":"Regulation of Protein Synthesis and Apoptosis in Lymphocytes of Parkinson Patients: The Effect of Dopaminergic Treatment","volume":"19","author":"Pain","year":"2019","journal-title":"Neurodegener. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12640-020-00182-4","article-title":"MPTP-Induced Impairment of Cardiovascular Function","volume":"38","author":"Liu","year":"2020","journal-title":"Neurotox. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"102667","DOI":"10.1016\/j.arr.2025.102667","article-title":"Oxidative stress and mitochondrial impairment: Key drivers in neurodegenerative disorders","volume":"104","author":"Wen","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref_4","first-page":"1489","article-title":"Antinociceptive effects of carbidopa levodopa on normal rats and Parkinson\u2019s disease mice","volume":"36","author":"Wenbo","year":"2023","journal-title":"Pak. J. Pharm. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/cpdd.1360","article-title":"Reduced Plasma Levodopa Fluctuations with More Frequent Administration of a Novel Carbidopa\/Levodopa Functionally Scored Tablet","volume":"13","author":"Chase","year":"2024","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1002\/term.3053","article-title":"Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases","volume":"14","author":"Guo","year":"2020","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gureev, A.P., Chernyshova, E.V., Krutskikh, E.P., Sadovnikova, I.S., Tekutskaya, E.E., and Dorohova, A.A. (2024). Role of the Nrf2\/ARE Pathway in the mtDNA Reparation. Front. Biosci., 29.","DOI":"10.31083\/j.fbl2906218"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S541","DOI":"10.33549\/physiolres.934612","article-title":"The Role of Nrf2 and PPAR\u03b3 in the Improvement of Oxidative Stress in Hypertension and Cardiovascular Diseases","volume":"69","author":"Dovinova","year":"2020","journal-title":"Physiol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.freeradbiomed.2020.03.023","article-title":"Beyond repression of Nrf2: An update on Keap1","volume":"157","author":"Kopacz","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1021\/acschemneuro.0c00713","article-title":"Ginnalin A Binds to the Subpockets of Keap1 Kelch Domain To Activate the Nrf2-Regulated Antioxidant Defense System in SH-SY5Y Cells","volume":"12","author":"Zhang","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_11","first-page":"785","article-title":"Activation of transcription factor Nrf2 to counteract mitochondrial dysfunction in Parkinson\u2019s disease","volume":"41","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref_12","first-page":"443","article-title":"Drug repurposing of dimethyl fumarate in Parkinson\u2019s disease: A promising disease-modifying strategy","volume":"29","author":"Gardoni","year":"2025","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6343","DOI":"10.1007\/s10072-025-08548-2","article-title":"Physical exercise and inflammation in Parkinson\u2019s disease: A review","volume":"46","author":"Han","year":"2025","journal-title":"Neurol. Sci."},{"key":"ref_14","first-page":"CD013856","article-title":"Physical exercise for people with Parkinson\u2019s disease: A systematic review and network meta-analysis","volume":"4","author":"Ernst","year":"2024","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117345","DOI":"10.1016\/j.lfs.2020.117345","article-title":"The benefits and mechanisms of exercise training for Parkinson\u2019s disease","volume":"245","author":"Feng","year":"2020","journal-title":"Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Palasz, E., Gasiorowska-Bien, A., Drapich, P., Niewiadomski, W., and Niewiadomska, G. (2025). Steady Moderate Exercise Confers Resilience Against Neurodegeneration and Neuroinflammation in a Mouse Model of Parkinson\u2019s Disease. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031146"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Palasz, E., Wysocka, A., Gasiorowska, A., Chalimoniuk, M., Niewiadomski, W., and Niewiadomska, G. (2020). BDNF as a Promising Therapeutic Agent in Parkinson\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031170"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.freeradbiomed.2020.08.016","article-title":"Aerobic exercise training partially reverses the impairment of Nrf2 activation in older humans","volume":"160","author":"Ostrom","year":"2020","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102830","DOI":"10.1016\/j.redox.2023.102830","article-title":"Limited expression of Nrf2 in neurons across the central nervous system","volume":"65","author":"Levings","year":"2023","journal-title":"Redox Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/s41582-024-01023-0","article-title":"Disease-modifying therapies for Parkinson disease: Lessons from multiple sclerosis","volume":"20","author":"Kalia","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_21","first-page":"2490","article-title":"Progress in Disease-Modifying Therapies for Parkinson\u2019s Disease","volume":"17","author":"Zhang","year":"2025","journal-title":"Aging Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mitchell, A.K., Bliss, R.R., and Church, F.C. (2024). Exercise, Neuroprotective Exerkines, and Parkinson\u2019s Disease: A Narrative Review. Biomolecules, 14.","DOI":"10.3390\/biom14101241"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.jare.2025.05.039","article-title":"Targeting the bile acid receptor TGR5 with Gentiopicroside to activate Nrf2 antioxidant signaling and mitigate Parkinson\u2019s disease in an MPTP mouse model","volume":"80","author":"Gao","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1093\/brain\/awq386","article-title":"Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway","volume":"134","author":"Linker","year":"2011","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102134","DOI":"10.1016\/j.redox.2021.102134","article-title":"The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson\u2019s disease","volume":"47","author":"Zhang","year":"2021","journal-title":"Redox Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7439\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T04:15:39Z","timestamp":1787372139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7439"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":25,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167439"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167439","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]}}}