{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:13:30Z","timestamp":1793146410962,"version":"4.5.0"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"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. Aging Neurosci."],"abstract":"<jats:p>\n                    Parkinson\u2019s Disease (PD) involves the loss of dopaminergic neurons and the formation of Lewy bodies consisting of alpha-synuclein (\u03b1Sin) aggregates. Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, has emerged as a molecule of interest due to pro-inflammatory, pro-oxidative, and neurodegenerative effects. We aim to assess whether lower doses of TMAO (40 mg\/kg bw, gavage, once daily, day 0\u201342), as those used in atherosclerosis experimental models, can exacerbate oxidative stress, neuroinflammation, motor dysfunction, and neurodegeneration in a semi-acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD model (30 mg\/kg bw MPTP, intraperitoneal, once daily, day 20\u201324). Motor behavioral testing functionally validated the model, with MPTP impairing performance across Rotarod latency time (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05), Wire Hang number of reaches and falls (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05), and Pole test time to descent (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.01 MPTP vs. Control,\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05 MPTP+TMAO vs. Control). A synergistic effect between TMAO and MPTP was observed in pole-turning time (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05). Increased TMAO serum was confirmed in treated animals (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05 TMAO vs. Control;\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.001 MPTP+TMAO vs. Control). Loss of tyrosine hydroxylase (TH) positive thalamic fibers, as well as substantia nigra neuronal fiber degeneration, and dopamine depletion was observed in the MPTP groups. A significant reduction in tyrosine hydroxylase (TH) expression in the midbrain was observed exclusively in the TMAO+MPTP group (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05 vs. Control). Neuroinflammatory profiling revealed selective elevation of IL-6 in the TMAO+MPTP group (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05), without microglial activation (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;gt; 0.05), whereas NF-\u03baB p65 was paradoxically increased only in the TMAO (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05) and MPTP (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05) groups. We hypothesize that this divergent pattern may indicate a shift toward necrotic rather than apoptotic cell death in the combined exposure group. MPTP and TMAO independently induced pro-oxidative states, evidenced by GSH depletion (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.0001 MPTP vs. Control;\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.001 MPTP+TMAO vs. Control) and compensatory SOD upregulation (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.01 TMAO vs. Control;\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05 MPTP vs. Control and MPTP+TMAO vs. Control). The combination amplified the redox imbalance with significant elevation of MDA in the TMAO+MPTP group (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.001 vs. Control and vs. TMAO;\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.01 vs. MPTP). These findings carry clinical relevance in the context of Parkinson\u2019s disease, suggesting that gut microbiome-derived metabolites may represent a pathological connection capable of increasing both cardiovascular risk and the progression of neurodegenerative disorders.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1871569","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:21:40Z","timestamp":1785331300000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Atherosclerotic-dose TMAO accentuates redox imbalances and motor dysfunctions in a MPTP mouse model of Parkinson\u2019s disease"],"prefix":"10.3389","volume":"18","author":[{"given":"Paul-\u015etefan","family":"Panaitescu","sequence":"first","affiliation":[{"name":"Department of Microbiology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"B\u00e2ldea","sequence":"additional","affiliation":[{"name":"Department of Physiology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad Alexandru","family":"Toma","sequence":"additional","affiliation":[{"name":"Department of Medical and Health Sciences Babes-Bolyai University","place":["Cluj-Napoca, Romania"]},{"name":"Biological Research Institute","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra-Maria","family":"Nu\u0163u","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babe\u015f-Bolyai University","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia-Andreea","family":"Moldoveanu","sequence":"additional","affiliation":[{"name":"Department of Medical and Health Sciences Babes-Bolyai University","place":["Cluj-Napoca, Romania"]},{"name":"Biological Research Institute","place":["Cluj-Napoca, Romania"]},{"name":"Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babe\u015f-Bolyai University","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Sevastre-Berghian","sequence":"additional","affiliation":[{"name":"Department of Physiology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Maria","family":"Vlase","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Botany, Faculty of Pharmacy, \u201cIuliu Ha\u0163ieganu\u201d University of Medicine and Pharmacy","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina Camelia","family":"Harangu\u015f","sequence":"additional","affiliation":[{"name":"Department of Physiology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Costache","sequence":"additional","affiliation":[{"name":"Department of Microbiology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Clichici","sequence":"additional","affiliation":[{"name":"Department of Physiology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela Adriana","family":"Filip","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Embriology, \u201cIuliu Ha\u0163ieganu\u201d University of Medicine and Pharmacy","place":["Cluj-Napoca, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.yexmp.2008.10.004","article-title":"Role of nuclear transcription factor kappa B (NF-kappaB) for MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine)-induced apoptosis in nigral neurons of mice.","volume":"86","author":"Aoki","year":"2009","journal-title":"Exp. 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