{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:56:01Z","timestamp":1780631761829,"version":"3.54.1"},"reference-count":111,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T00:00:00Z","timestamp":1600387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 105-2313-B-033-001-MY3 and MOST 107-2622-B-033-001-CC2 to C.-D.H"],"award-info":[{"award-number":["MOST 105-2313-B-033-001-MY3 and MOST 107-2622-B-033-001-CC2 to C.-D.H"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2113-M153-003 to K.H.-C.C."],"award-info":[{"award-number":["MOST 108-2113-M153-003 to K.H.-C.C."]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Donepezil (DPZ) is an acetylcholinesterase inhibitor used for the clinical treatment of mild cognitive impairment. However, DPZ has been reported to have adverse effects, including causing abnormal cardiac rhythm, insomnia, vomiting, and muscle cramps. However, the existence of these effects in subjects without Dementia is unknown. In this study, we use zebrafish to conduct a deeper analysis of the potential adverse effects of DPZ on the short-term memory and behaviors of normal zebrafish by performing multiple behavioral and biochemical assays. Adult zebrafish were exposed to 1 ppm and 2.5 ppm of DPZ. From the results, DPZ caused a slight improvement in the short-term memory of zebrafish and induced significant elevation in aggressiveness, while the novel tank and shoaling tests revealed anxiolytic-like behavior to be caused by DPZ. Furthermore, zebrafish circadian locomotor activity displayed a higher reduction of locomotion and abnormal movement orientation in both low- and high-dose groups, compared to the control group. Biomarker assays revealed that these alterations were associated with an elevation of oxytocin and a reduction of cortisol levels in the brain. Moreover, the significant increases in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in muscle tissue suggest DPZ exposure induced muscle tissue oxidative stress and muscle weakness, which may underlie the locomotor activity impairment. In conclusion, we show, for the first time, that chronic waterborne exposure to DPZ can severely induce adverse effects on normal zebrafish in a dose-dependent manner. These unexpected adverse effects on behavioral alteration should be carefully addressed in future studies considering DPZ conducted on zebrafish or other animals.<\/jats:p>","DOI":"10.3390\/biom10091340","type":"journal-article","created":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T07:06:09Z","timestamp":1600499169000},"page":"1340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments"],"prefix":"10.3390","volume":"10","author":[{"given":"Gilbert","family":"Audira","sequence":"first","affiliation":[{"name":"Department of Chemistry, Chung Yuan Christian University, Chung-Li 320314, Taiwan"},{"name":"Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 320314, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Thi","family":"Ngoc Anh","sequence":"additional","affiliation":[{"name":"Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 320314, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bui Thi","family":"Ngoc Hieu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Chung Yuan Christian University, Chung-Li 320314, Taiwan"},{"name":"Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 320314, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nemi","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Chung Yuan Christian University, Chung-Li 320314, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petrus","family":"Siregar","sequence":"additional","affiliation":[{"name":"Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 320314, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1856-1087","authenticated-orcid":false,"given":"Omar","family":"Villalobos","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, University of Santo Tomas, Manila 1008, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver B.","family":"Villaflores","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, University of Santo Tomas, Manila 1008, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzong-Rong","family":"Ger","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Chung Yuan Christian University, Chung-Li 320314, Taiwan"},{"name":"Center of Nanotechnology, Chung Yuan Christian University, Chung-Li 320314, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3997-1683","authenticated-orcid":false,"given":"Jong-Chin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry, National Pingtung University, Pingtung 900391, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin H.-C.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry, National Pingtung University, Pingtung 900391, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6398-8672","authenticated-orcid":false,"given":"Chung-Der","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Chung Yuan Christian University, Chung-Li 320314, Taiwan"},{"name":"Department of Biomedical Engineering, Chung Yuan Christian University, Chung-Li 320314, Taiwan"},{"name":"Center of Nanotechnology, Chung Yuan Christian University, Chung-Li 320314, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,18]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2019). 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