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
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 i...
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MDPI AG
2022-05-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/5/908 |
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| author | Yuan Zhang Tun Sun Meng Li Yanling Lin Yue Liu Shusheng Tang Chongshan Dai |
| author_facet | Yuan Zhang Tun Sun Meng Li Yanling Lin Yue Liu Shusheng Tang Chongshan Dai |
| author_sort | Yuan Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T03:26:30Z |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T03:26:30Z |
| publishDate | 2022-05-01 |
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| series | Antioxidants |
| spelling | doaj.art-97ef8f8b99a74c698d6daee47a0ec8012023-11-23T09:51:33ZengMDPI AGAntioxidants2076-39212022-05-0111590810.3390/antiox11050908Ivermectin-Induced Apoptotic Cell Death in Human SH-SY5Y Cells Involves the Activation of Oxidative Stress and Mitochondrial Pathway and Akt/mTOR-Pathway-Mediated AutophagyYuan Zhang0Tun Sun1Meng Li2Yanling Lin3Yue Liu4Shusheng Tang5Chongshan Dai6College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaCollege of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaCollege of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaCollege of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaCollege of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaCollege of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaCollege of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, ChinaIvermectin (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.https://www.mdpi.com/2076-3921/11/5/908ivermectinneurotoxicityoxidative stressapoptosisautophagyAkt/mTOR pathway |
| spellingShingle | Yuan Zhang Tun Sun Meng Li Yanling Lin Yue Liu Shusheng Tang Chongshan Dai 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 ivermectin neurotoxicity oxidative stress apoptosis autophagy Akt/mTOR pathway |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | ivermectin neurotoxicity oxidative stress apoptosis autophagy Akt/mTOR pathway |
| url | https://www.mdpi.com/2076-3921/11/5/908 |
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