{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:41:42Z","timestamp":1791294102619,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacy"],"abstract":"<jats:p>Exercise-induced myokines have emerged as crucial mediators of the beneficial effects of physical activity on neurodegenerative diseases through complex molecular mechanisms involving oxidative stress reduction, neuroinflammation suppression, and synaptic plasticity enhancement. Among these myokines, irisin, encoded by the FNDC5 gene, has gained significant attention as a potential therapeutic target in neurodegenerative conditions due to its ability to cross the blood\u2013brain barrier and exert pleiotropic neuroprotective effects. This review synthesizes current evidence from both preclinical and clinical studies examining the role of exercise-induced irisin in neurodegeneration, with particular emphasis on translational potential and therapeutic applications. A comprehensive search was conducted across PubMed, Web of Science, Scopus, and EMBASE databases (spanning January 2015 to December 2024) to identify peer-reviewed articles investigating irisin\u2019s neuroprotective mechanisms in neurodegenerative diseases. Ten studies met the inclusion criteria (five rodent\/primate model studies and five human clinical investigations), which were analyzed for methodological rigor, intervention protocols, biomarker quantification methods, and reported outcomes. Reviewed studies consistently demonstrated that exercise-induced endogenous irisin elevation correlates with improved cognitive function, reduced neuroinflammatory markers, enhanced synaptic plasticity, and modulation of neurodegenerative pathways, with exogenous irisin administration reproducing several neuroprotective benefits observed with exercise training in animal models. However, substantial heterogeneity exists regarding exercise prescription parameters (intensity, duration, frequency, modality), training-induced irisin quantification methodologies (ELISA versus mass spectrometry), and study designs (ranging from uncontrolled human observations to randomized controlled trials in animal models). Critical appraisal reveals that human studies lack adequate control for confounding variables including baseline physical fitness, comorbidities, concurrent medications, and potential sources of bias, while biochemical studies indicate distinct pharmacokinetics between endogenous training-induced irisin and exogenous bolus dosing, necessitating careful interpretation of therapeutic applicability. The translational potential of irisin as a therapeutic agent or drug target depends on resolving methodological standardization in biomarker measurement, conducting well-designed clinical trials with rigorous control for confounders, and integrating findings from molecular\/biochemical studies to elucidate mechanisms linking irisin to disease modification. Future research should prioritize establishing clinical trial frameworks that harmonize exercise prescriptions, employ robust biomarker quantification (mass spectrometry), and stratify participants based on disease stage, comorbidities, and genetic predisposition to clarify irisin\u2019s role as a potential therapeutic intervention in neurodegenerative disease management.<\/jats:p>","DOI":"10.3390\/pharmacy14010009","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T09:27:12Z","timestamp":1768296432000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Irisin as a Neuroprotective Agent in Parkinson\u2019s Disease: The Role of Physical Exercise in Modulating Dopaminergic Neurons"],"prefix":"10.3390","volume":"14","author":[{"given":"Jos\u00e9 Garcia","family":"de Brito-Neto","sequence":"first","affiliation":[{"name":"Laboratory Experimental Neurology, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte (UERN), Mossor\u00f3 59607-360, Brazil"},{"name":"Postgraduate Program in Physiological Sciences, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte (UERN), Mossor\u00f3 59607-360, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo Leonardo de G\u00f3is","family":"Morais","sequence":"additional","affiliation":[{"name":"Laboratory Experimental Neurology, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte (UERN), Mossor\u00f3 59607-360, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1554-3249","authenticated-orcid":false,"given":"Jos\u00e9 Rodolfo Lopes de Paiva","family":"Cavalcanti","sequence":"additional","affiliation":[{"name":"Laboratory Experimental Neurology, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte (UERN), Mossor\u00f3 59607-360, Brazil"},{"name":"Postgraduate Program in Physiological Sciences, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte (UERN), Mossor\u00f3 59607-360, Brazil"},{"name":"Postgraduate Program in Health and Society, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte(UERN), Mossor\u00f3 59607-360, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8879-3997","authenticated-orcid":false,"given":"Francisco Irochima","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Biotechnology, Health School, Potiguar University (UnP), Natal 59056-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fausto Pierdon\u00e1","family":"Guzen","sequence":"additional","affiliation":[{"name":"Laboratory Experimental Neurology, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte (UERN), Mossor\u00f3 59607-360, Brazil"},{"name":"Postgraduate Program in Physiological Sciences, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte (UERN), Mossor\u00f3 59607-360, Brazil"},{"name":"Postgraduate Program in Health and Society, Department of Biomedical Sciences, Faculty of Health Sciences, State University of Rio Grande do Norte(UERN), Mossor\u00f3 59607-360, Brazil"},{"name":"Postgraduate Program in Biotechnology, Health School, Potiguar University (UnP), Natal 59056-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0184-2061","authenticated-orcid":false,"given":"Ricardo Ney","family":"Cobucci","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Biotechnology, Health School, Potiguar University (UnP), Natal 59056-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","first-page":"153","article-title":"Muscle-derived interleukins and other cytokines in exercise and trained states: An update","volume":"19","author":"Pedersen","year":"2023","journal-title":"Nat. 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