{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:39:22Z","timestamp":1790717962993,"version":"4.1.0"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Parkinson\u2019s disease (PD) is caused by the progressive loss of dopaminergic neurons in the substantia nigra. Neuroinflammation is considered a key factor contributing to the pathophysiology of PD. Current gold-standard therapies for PD provide only symptomatic relief without slowing disease progression, highlighting the need to develop new disease-modifying treatments. Metformin has been demonstrated to exert a neuroprotective role in several neurodegenerative disorders including PD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>This study aimed to clarify the role of metformin as adjuvant therapy in patients with PD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sixty patients with PD were divided into 2 groups (n = 30). Patients in group 1 received levodopa\/carbidopa (250\/25\u00a0mg) three times daily for 3\u00a0months plus placebo (Control group), while those in group 2 received levodopa\/carbidopa (250\/25\u00a0mg) three times daily and 500\u00a0mg metformin two times daily (Metformin group). Patients were assessed via Unified Parkinson\u2019s Disease Rating Scale (UPDRS). The serum concentrations of toll like receptor 4 (TLR-4), \u03b1-synuclein, brain derived neurotropic factor (BDNF), and high mobility group box 1 (HMGB-1) were measured before and after treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Primary outcome<\/jats:title><jats:p>The improvement in UPDRS from baseline to 3\u00a0months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Secondary outcome<\/jats:title><jats:p>Change in the level of biological markers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The control group did not show significant difference in UPDRS when compared to their baseline value by Wilcoxon test (<jats:italic>P<\/jats:italic> &amp;gt; 0.05), meanwhile the metformin group showed significant difference when compared to before treatment by Wilcoxon test (<jats:italic>P<\/jats:italic> &amp;lt; 0.05). There were no significant differences between the two groups in UPDRS after treatment (<jats:italic>P<\/jats:italic> &amp;gt; 0.05) by Man Whitney test. However, the metformin group showed a significant decrease in TLR-4, HMGB-1, and \u03b1-synuclein along with a statistically significant increase in BDNF (<jats:italic>P<\/jats:italic> &amp;lt; 0.05) when compared to its baseline and control group. The control group did not show any significant changes in all markers when compared to their baseline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>While no significant differences in UPDRS scores were observed between the metformin and control groups, trends in biomarker changes suggest a potential impact of adjunctive metformin use on the underlying pathophysiology of PD. Further studies are needed to assess its effects on motor symptoms over a longer duration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Trial Registration<\/jats:title><jats:p>identifier NCT05781711.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1497261","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:48:21Z","timestamp":1746186501000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Randomized, double-blind, placebo-controlled pilot study of metformin as an adjunctive therapy in Parkinson\u2019s disease"],"prefix":"10.3389","volume":"16","author":[{"given":"Hayam Ali","family":"AlRasheed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa M.","family":"Bahaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanaa A.","family":"Elmasry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman I.","family":"Elberri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fedaa A.","family":"Kotkata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramy M.","family":"El Sabaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine M.","family":"Elmorsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa M.","family":"Kamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walaa A.","family":"Negm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir O.","family":"Hamouda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khlood Mohammad","family":"Aldossary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammed M.","family":"Salahuddin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Yasser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamdouh","family":"Eldesouqui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal A.","family":"Hamouda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nashwa","family":"Eltantawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirna E.","family":"Elawady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud S.","family":"Abdallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1007\/s00415-023-12113-2","article-title":"The impact of metformin use on the outcomes of relapse-remitting multiple sclerosis patients receiving interferon beta 1a: an exploratory prospective phase II open-label randomized controlled trial","volume":"271","author":"Abdelgaied","year":"2024","journal-title":"J. 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