{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:53:50Z","timestamp":1777949630648,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T00:00:00Z","timestamp":1777680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangxi Science and Technology Major Program","award":["GUIKEJF2504850033"],"award-info":[{"award-number":["GUIKEJF2504850033"]}]},{"name":"\u201cDai Tu Yi Zhi\u201d Project of Key R & D Program of Guangxi","award":["GUIKE AA25069003"],"award-info":[{"award-number":["GUIKE AA25069003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Depression is a complex mental and neurological disorder and has become one of the most serious public health issues in modern society. Trihexyphenidyl (THY) is a traditional drug used to treat Parkinson\u2019s disease. Recent studies have suggested that it may play a role in regulating neurotransmitters and protecting neurons, but its potential for treating depression has not been fully explored, and how it works remains unclear. Therefore, we examined the effects of THY on depression-like behaviors in zebrafish caused by chronic unpredictable stress (CUS). Our results showed that THY significantly attenuated the CUS-induced decrease in exploratory behavior and shortened the CUS-induced increase in latency time. At the tissue level, THY effectively attenuated the thinning of the optic tectum and the loss of Nissl bodies caused by CUS. In addition, THY reversed the CUS-induced increase in stress hormone levels and reduction in neurotransmitter content. Through network pharmacology and transcriptome sequencing analysis, we found that the mechanisms underlying depression-like behaviors and the antidepressant effects of THY might be related to the MAPK signaling pathway. Further experiments showed that THY regulated the CUS-induced activation of the MAPK signaling pathway, improved the abnormal activation of microglia and damage to astrocytes, and reduced the expression of pro-inflammatory factors, thereby easing neuroinflammation and improving depression-like behaviors. In summary, this study explored the potential mechanism of THY ameliorating depressive-like behaviors and provided basic theoretical evidence.<\/jats:p>","DOI":"10.3390\/biom16050678","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:06:21Z","timestamp":1777860381000},"page":"678","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trihexyphenidyl Ameliorates Depression-like Behaviors in Adult Zebrafish Exposed to Chronic Unpredictable Stress, Consistent with Regulation of the MAPK Signaling Pathway"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6507-2651","authenticated-orcid":false,"given":"Siqi","family":"Hu","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yedong","family":"Yao","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leqing","family":"Zhan","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rihua","family":"Feng","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongting","family":"Zhangsun","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-5970","authenticated-orcid":false,"given":"Sulan","family":"Luo","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8830-4954","authenticated-orcid":false,"given":"Xiaopeng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jpsychires.2019.08.002","article-title":"Changes in the global burden of depression from 1990 to 2017: Findings from the Global Burden of Disease study","volume":"126","author":"Liu","year":"2020","journal-title":"J. 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