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Antioxidants
Volume 11
Issue 5
10.3390/antiox11050908
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Article

Ivermectin-Induced Apoptotic Cell Death in Human SH-SY5Y Cells Involves the Activation of Oxidative Stress and Mitochondrial Pathway and Akt/mTOR-Pathway-Mediated Autophagy

by
Yuan Zhang
1,
Tun Sun
1,
Meng Li
1,
Yanling Lin
1,
Yue Liu
1,
Shusheng Tang
1,2,* and
Chongshan Dai
1,2,3,*
1
College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China
2
Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
3
Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
*
Authors to whom correspondence should be addressed.
Antioxidants 2022, 11(5), 908; https://doi.org/10.3390/antiox11050908
Submission received: 30 March 2022 / Revised: 30 April 2022 / Accepted: 3 May 2022 / Published: 5 May 2022
(This article belongs to the Special Issue Antioxidants, Oxidative Stress and Non-communicable Diseases)
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Abstract

Ivermectin (IVM) could cause potential neurotoxicity; however, the precise molecular mechanisms remain unclear. This study explores the cytotoxicity of IVM in human neuroblastoma (SH-SY5Y) cells and the underlying molecular mechanisms. The results show that IVM treatment (2.5–15 μM) for 24 h could induce dose-dependent cell death in SH-SY5Y cells. Compared to the control, IVM treatment significantly promoted the production of ROS, mitochondrial dysfunction, and cell apoptosis. IVM treatment also promoted mitophagy and autophagy, which were charactered by the decreased expression of phosphorylation (p)-Akt and p-mTOR proteins, increased expression of LC3II, Beclin1, ATG5, PINK, and Pakin1 proteins and autophagosome formation. N-acetylcysteine treatment significantly inhibited the IVM-induced production of ROS and cell death in SH-SY5Y cells. Autophagy inhibitor (e.g., 3-methyladenine) treatment significantly inhibited IVM-induced autophagy, oxidative stress, and cell apoptosis. Taken together, our results reveal that IVM could induce autophagy and apoptotic cell death in SH-SY5Y cells, which involved the production of ROS, activation of mitochondrial pathway, and inhibition of Akt/mTOR pathway. Autophagy inhibition improved IVM-induced oxidative stress and apoptotic cell death in SH-SY5Y cells. This current study provides new insights into understanding the molecular mechanism of IVM-induced neurotoxicity and facilitates the discovery of potential neuroprotective agents.
Keywords: ivermectin; neurotoxicity; oxidative stress; apoptosis; autophagy; Akt/mTOR pathway ivermectin; neurotoxicity; oxidative stress; apoptosis; autophagy; Akt/mTOR pathway

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MDPI and ACS Style

Zhang, Y.; Sun, T.; Li, M.; Lin, Y.; Liu, Y.; Tang, S.; Dai, C. Ivermectin-Induced Apoptotic Cell Death in Human SH-SY5Y Cells Involves the Activation of Oxidative Stress and Mitochondrial Pathway and Akt/mTOR-Pathway-Mediated Autophagy. Antioxidants 2022, 11, 908. https://doi.org/10.3390/antiox11050908

AMA Style

Zhang Y, Sun T, Li M, Lin Y, Liu Y, Tang S, Dai C. Ivermectin-Induced Apoptotic Cell Death in Human SH-SY5Y Cells Involves the Activation of Oxidative Stress and Mitochondrial Pathway and Akt/mTOR-Pathway-Mediated Autophagy. Antioxidants. 2022; 11(5):908. https://doi.org/10.3390/antiox11050908

Chicago/Turabian Style

Zhang, Yuan, Tun Sun, Meng Li, Yanling Lin, Yue Liu, Shusheng Tang, and Chongshan Dai. 2022. "Ivermectin-Induced Apoptotic Cell Death in Human SH-SY5Y Cells Involves the Activation of Oxidative Stress and Mitochondrial Pathway and Akt/mTOR-Pathway-Mediated Autophagy" Antioxidants 11, no. 5: 908. https://doi.org/10.3390/antiox11050908

APA Style

Zhang, Y., Sun, T., Li, M., Lin, Y., Liu, Y., Tang, S., & Dai, C. (2022). Ivermectin-Induced Apoptotic Cell Death in Human SH-SY5Y Cells Involves the Activation of Oxidative Stress and Mitochondrial Pathway and Akt/mTOR-Pathway-Mediated Autophagy. Antioxidants, 11(5), 908. https://doi.org/10.3390/antiox11050908

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