{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T12:00:10Z","timestamp":1777636810815,"version":"3.51.4"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"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>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Rosmarinic acid (RA), gallic acid (GA), and 3-hydroxytyrosol (3-HT) are phenolic compounds abundant in medicinal plants traditionally used to support cognitive function and neurological wellbeing. Although their antioxidant and neuroprotective properties are well documented in mammalian systems, their behavioral effects remain insufficiently explored in alternative\n                      <jats:italic>in vivo<\/jats:italic>\n                      models relevant for ethnopharmacological screening.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we investigated the anxiolytic and cognitive-enhancing potential of RA, GA, and 3-HT in adult zebrafish (\n                      <jats:italic>Danio rerio<\/jats:italic>\n                      ). Compounds were administered by immersion (3\u00a0\u03bcg\/L, once daily for 8 days). Anxiety-related behaviors were evaluated using the novel tank diving test (NTT). At the same time, cognitive performance was assessed using the Y-maze and novel object recognition (NOR) tests to examine spatial and recognition memory, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RA significantly increased the top\/bottom time ratio (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.0001), indicating reduced anxiety_like behavior; however, this effect was accompanied by reductions in locomotor activity (distance traveled,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.05; swimming velocity,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.01), suggesting a possible sedative component. In contrast, GA and 3-HT elicited anxiety_like behavioral responses in the NTT without significantly affecting locomotion. Despite their anxiogenic profile, GA and 3-HT significantly enhanced spatial memory in the Y_maze test (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001), whereas RA and 3-HT increased exploration of the novel arm (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001). Moreover, 3-HT significantly improved recognition memory in the NOR test (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Together, these findings reveal distinct neurobehavioral profiles for each phenolic compound: RA exhibited pronounced anxiolytic activity, while GA and 3-HT primarily enhanced cognitive performance, with 3-HT exerting broad-spectrum memory-facilitating effects. Overall, these results underscore the value of zebrafish as a translational model for behavioral pharmacology and support the ethnopharmacological relevance of RA, GA, and 3-HT as potential candidates for further investigation in the context of anxiety and cognitive disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1801073","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T05:54:15Z","timestamp":1777442055000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Anxiolytic and cognitive effects of dietary phenolics in zebrafish: rosmarinic acid, gallic acid, and 3-hydroxytyrosol"],"prefix":"10.3389","volume":"17","author":[{"given":"Tugba","family":"Ucar Akyurek","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Gazi University","place":["Ankara, T\u00fcrkiye"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilkay Erdogan","family":"Orhan","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Gazi University","place":["Ankara, T\u00fcrkiye"]},{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Lokman Hekim University","place":["Ankara, T\u00fcrkiye"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatma Sezer","family":"Senol Deniz","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Gazi University","place":["Ankara, T\u00fcrkiye"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ion","family":"Brinza","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, Lucian Blaga University of Sibiu","place":["Sibiu, Romania"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Razvan Stefan","family":"Boiangiu","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi","place":["Iasi, Romania"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucian","family":"Hritcu","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi","place":["Iasi, Romania"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1007\/S10787-025-01699-W\/METRICS","article-title":"Gallic acid enhances memory, learning and reduces neuroinflammation in a rat model of scopolamine-induced cholinergic dysfunction","volume":"33","author":"Alikhanzade","year":"2025","journal-title":"Inflammopharmacology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5570","DOI":"10.3390\/IJMS20225570","article-title":"Natural products and neuroprotection","volume":"20","author":"Angeloni","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1892","DOI":"10.3390\/IJMS25031892","article-title":"Enemies or allies? Hormetic and apparent non-dose-dependent effects of natural bioactive antioxidants in the treatment of inflammation","volume":"25","author":"Barreiro-Sisto","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9781139344319","volume-title":"The design and statistical analysis of animal experiments","author":"Bate","year":"2014"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.3390\/PLANTS11081096","article-title":"Angelica purpurascens (Av\u00e9-Lall.) gilli. Essential oil improved brain function via cholinergic modulation and antioxidant effects in the scopolamine-induced zebrafish (Danio rerio) model","volume":"11","author":"Boiangiu","year":"2022","journal-title":"Plants (Basel)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1786","DOI":"10.1038\/nprot.2010.140","article-title":"Measuring behavioral and endocrine responses to novelty stress in adult zebrafish","volume":"5","author":"Cachat","year":"2010","journal-title":"Nat. Protoc."},{"key":"B7","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.taap.2004.02.007","article-title":"Hormesis: from marginalization to mainstream. A case for hormesis as the default dose-response model in risk assessment","volume":"197","author":"Calabrese","year":"2004","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"7085","DOI":"10.3390\/MOLECULES26237085","article-title":"Origanum vulgare ssp. Hirtum (lamiaceae) essential oil prevents behavioral and oxidative stress changes in the scopolamine zebrafish model","volume":"26","author":"Capatina","year":"2021","journal-title":"Molecules"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e1534","DOI":"10.1016\/S2214-109X(24)00264-X","article-title":"The global macroeconomic burden of Alzheimer\u2019s disease and other dementias: estimates and projections for 152 countries or territories","volume":"12","author":"Chen","year":"2024","journal-title":"Lancet Glob. Health"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3082","DOI":"10.3390\/IJMS19103082","article-title":"Neuronal cell death mechanisms in major neurodegenerative diseases","volume":"19","author":"Chi","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"155101","DOI":"10.1016\/J.PHYMED.2023.155101","article-title":"Natural products for the treatment of neurodegenerative diseases","volume":"121","author":"Cui","year":"2023","journal-title":"Phytomedicine"},{"key":"B12","doi-asserted-by":"publisher","first-page":"952161","DOI":"10.3389\/FPUBH.2022.952161\/PDF","article-title":"Global, regional, and national burden and attributable risk factors of neurological disorders: the global burden of disease study 1990\u20132019","volume":"10","author":"Ding","year":"2022","journal-title":"Front. Public Health"},{"key":"B13","doi-asserted-by":"publisher","first-page":"a028035","DOI":"10.1101\/CSHPERSPECT.A028035","article-title":"Pathology of neurodegenerative diseases","volume":"9","author":"Dugger","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"102070","DOI":"10.1016\/j.arr.2023.102070","article-title":"The blood-brain barrier, a key bridge to treat neurodegenerative diseases","volume":"91","author":"Hang","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1111\/DOM.16130","article-title":"Investigating the common genetic architecture and causality of metabolic disorders with neurodegenerative diseases","volume":"27","author":"Hong","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"B16","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1002\/CPT.209","article-title":"Pharmacotherapy for neurodegenerative diseases: are we approaching the tipping point?","volume":"98","author":"Honig","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/NATURE05292","article-title":"Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases","volume":"443","author":"Lin","year":"2006","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1325932","DOI":"10.3389\/FPHAR.2023.1325932\/BIBTEX","article-title":"Comparative analysis of the metabolites and biotransformation pathways of fentanyl in the liver and brain of zebrafish","volume":"14","author":"Liu","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/J.CMET.2023.12.022","article-title":"The hormesis principle of neuroplasticity and neuroprotection","volume":"36","author":"Mattson","year":"2024","journal-title":"Cell Metab."},{"key":"B20","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1089\/ZEB.2015.1188","article-title":"A model of excitotoxic brain injury in larval zebrafish: potential application for high-throughput drug evaluation to treat traumatic brain injury","volume":"13","author":"McCutcheon","year":"2016","journal-title":"Zebrafish"},{"key":"B21","doi-asserted-by":"publisher","first-page":"16251","DOI":"10.1074\/jbc.RA119.012330","article-title":"Gallic acid is a dual \u03b1\/\u03b2-secretase modulator that reverses cognitive impairment and remediates pathology in alzheimer mice","volume":"295","author":"Mori","year":"2020","journal-title":"J. Biol. Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1002\/DTA.3590;PAGEGROUP:STRING:PUBLICATION","article-title":"Study of metabolism and potential toxicity of nine synthetic opioid analogs using the zebrafish larvae model","volume":"16","author":"Murari","year":"2024","journal-title":"Drug Test. Anal."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1002\/dta.2523","article-title":"Zebrafish (Danio rerio) water tank model for the investigation of drug metabolism: progress, outlook, and challenges","volume":"10","author":"Sardela","year":"2018","journal-title":"Drug Test. Anal."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1038\/S41593-018-0235-9","article-title":"Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases","volume":"21","author":"Soto","year":"2018","journal-title":"Nat. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"5938","DOI":"10.3390\/IJMS23115938","article-title":"An overview of oxidative stress, neuroinflammation and neurodegenerative diseases","volume":"23","author":"Teleanu","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.3390\/PH17111441","article-title":"Evaluation of selected plant phenolics via beta-secretase-1 inhibition, molecular docking, and gene expression related to Alzheimer\u2019s disease","volume":"17","author":"Ucar Akyurek","year":"2024","journal-title":"Pharmaceuticals"},{"key":"B28","doi-asserted-by":"publisher","first-page":"191","DOI":"10.26650\/IstanbulJPharm.2025.1533301","article-title":"Antioxidant profiling, in silico toxicity, and virtual bioactivity assessment of selected plant-derived phenolics","volume":"55","author":"Ucar Akyurek","year":"2025","journal-title":"Istanbul J. Pharm."},{"key":"B29","doi-asserted-by":"publisher","first-page":"108484","DOI":"10.1016\/j.bioorg.2025.108484","article-title":"A novel hydroxytyrosol derivative HT-3 enhances antioxidant and neuroprotective activity through efficient molecular conjugation","volume":"161","author":"Zhang","year":"2025","journal-title":"Bioorg. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"104823","DOI":"10.1016\/j.tiv.2020.104823","article-title":"Rosmarinic acid protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity in zebrafish embryos","volume":"65","author":"Zhao","year":"2020","journal-title":"Toxicol. Vitro"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1801073\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T05:54:16Z","timestamp":1777442056000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1801073\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":30,"alternative-id":["10.3389\/fphar.2026.1801073"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1801073","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]},"article-number":"1801073"}}