Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments

Audira, Gilbert; Ngoc Anh, Nguyen Thi; Ngoc Hieu, Bui Thi; Malhotra, Nemi; Siregar, Petrus; Villalobos, Omar; Villaflores, Oliver B.; Ger, Tzong-Rong; Huang, Jong-Chin; Chen, Kelvin H.-C.; Hsiao, Chung-Der

doi:10.3390/biom10091340

Open AccessArticle

Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments

by

Gilbert Audira

^1,2,†,

Nguyen Thi Ngoc Anh

^2,†,

Bui Thi Ngoc Hieu

^1,2,

Nemi Malhotra

³,

Petrus Siregar

²,

Omar Villalobos

⁴

,

Oliver B. Villaflores

⁵,

Tzong-Rong Ger

^3,6,

Jong-Chin Huang

⁷

,

Kelvin H.-C. Chen

^7,* and

Chung-Der Hsiao

^1,3,6,*

¹

Department of Chemistry, Chung Yuan Christian University, Chung-Li 320314, Taiwan

²

Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 320314, Taiwan

³

Department of Biomedical Engineering, Chung Yuan Christian University, Chung-Li 320314, Taiwan

⁴

Department of Pharmacy, Faculty of Pharmacy, University of Santo Tomas, Manila 1008, Philippines

⁵

Department of Biochemistry, Faculty of Pharmacy, University of Santo Tomas, Manila 1008, Philippines

⁶

Center of Nanotechnology, Chung Yuan Christian University, Chung-Li 320314, Taiwan

⁷

Department of Applied Chemistry, National Pingtung University, Pingtung 900391, Taiwan

^*

Authors to whom correspondence should be addressed.

^†

Equal contribution authors.

Biomolecules 2020, 10(9), 1340; https://doi.org/10.3390/biom10091340

Submission received: 1 September 2020 / Accepted: 17 September 2020 / Published: 18 September 2020

(This article belongs to the Special Issue Cholinesterase Research)

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Abstract

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.

Keywords: donepezil; acetylcholinesterase inhibitor; dementia; zebrafish; behavior

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MDPI and ACS Style

Audira, G.; Ngoc Anh, N.T.; Ngoc Hieu, B.T.; Malhotra, N.; Siregar, P.; Villalobos, O.; Villaflores, O.B.; Ger, T.-R.; Huang, J.-C.; Chen, K.H.-C.; et al. Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments. Biomolecules 2020, 10, 1340. https://doi.org/10.3390/biom10091340

AMA Style

Audira G, Ngoc Anh NT, Ngoc Hieu BT, Malhotra N, Siregar P, Villalobos O, Villaflores OB, Ger T-R, Huang J-C, Chen KH-C, et al. Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments. Biomolecules. 2020; 10(9):1340. https://doi.org/10.3390/biom10091340

Chicago/Turabian Style

Audira, Gilbert, Nguyen Thi Ngoc Anh, Bui Thi Ngoc Hieu, Nemi Malhotra, Petrus Siregar, Omar Villalobos, Oliver B. Villaflores, Tzong-Rong Ger, Jong-Chin Huang, Kelvin H.-C. Chen, and et al. 2020. "Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments" Biomolecules 10, no. 9: 1340. https://doi.org/10.3390/biom10091340

APA Style

Audira, G., Ngoc Anh, N. T., Ngoc Hieu, B. T., Malhotra, N., Siregar, P., Villalobos, O., Villaflores, O. B., Ger, T.-R., Huang, J.-C., Chen, K. H.-C., & Hsiao, C.-D. (2020). Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments. Biomolecules, 10(9), 1340. https://doi.org/10.3390/biom10091340

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Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments

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