Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation
Tahir Ali
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Search for more papers by this authorShafiq Ur Rahman
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Department of Pharmacy, Shaheed Benazir Bhutto University, Sheringal Dir, Pakistan
Search for more papers by this authorQiang Hao
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Search for more papers by this authorWeifen Li
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Search for more papers by this authorZizhen Liu
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Search for more papers by this authorFawad Ali Shah
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad., Islamabad, Pakistan
Search for more papers by this authorIram Murtaza
Signal Transduction Lab, Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan
Search for more papers by this authorZaijun Zhang
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University College of Pharmacy, Guangzhou, China
Search for more papers by this authorXifei Yang
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
Search for more papers by this authorGongping Liu
Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
Search for more papers by this authorCorresponding Author
Shupeng Li
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Correspondence
Shupeng Li, State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Email: [email protected]
Search for more papers by this authorTahir Ali
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Search for more papers by this authorShafiq Ur Rahman
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Department of Pharmacy, Shaheed Benazir Bhutto University, Sheringal Dir, Pakistan
Search for more papers by this authorQiang Hao
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Search for more papers by this authorWeifen Li
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Search for more papers by this authorZizhen Liu
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Search for more papers by this authorFawad Ali Shah
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad., Islamabad, Pakistan
Search for more papers by this authorIram Murtaza
Signal Transduction Lab, Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan
Search for more papers by this authorZaijun Zhang
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University College of Pharmacy, Guangzhou, China
Search for more papers by this authorXifei Yang
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
Search for more papers by this authorGongping Liu
Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
Search for more papers by this authorCorresponding Author
Shupeng Li
State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Correspondence
Shupeng Li, State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Email: [email protected]
Search for more papers by this authorFunding information
This work was supported by the Grants Science and Technology Innovation Committee of Shenzhen No: JCYJ20170810163329510. 2019SHIBS0004.
Abstract
Major depressive disorder (MDD) is a life-threatening illness characterized by mood changes and high rates of suicide. Although the role of neuroinflammation in MMD has been studied, the mechanistic interplay between antidepressants, neuroinflammation, and autophagy is yet to be investigated. The present study investigated the effect of melatonin on LPS-induced neuroinflammation, depression, and autophagy impairment. Our results showed that in mice, lipopolysaccharide (LPS) treatment induced depressive-like behaviors and caused autophagy impairment by dysregulating ATG genes. Moreover, LPS treatment significantly increased the levels of cytokines (TNFα, IL-1β, IL-6), enhanced NF-ᴋB phosphorylation, caused glial (astrocytes and microglia) cell activation, dysregulated FOXO3a expression, increased the levels of redox signaling molecules such as ROS/TBARs, and altered expression of Nrf2, SOD2, and HO-1. Melatonin treatment significantly abolished the effects of LPS, as demonstrated by improved depressive-like behaviors, normalized autophagy-related gene expression, and reduced levels of cytokines. Further, we investigated the role of autophagy in LPS-induced depressive-like behavior and neuroinflammation using autophagy inhibitors 3-MA and Ly294002. Interestingly, inhibitor treatment significantly abolished and reversed the anti-depressive, pro-autophagy, and anti-inflammatory effects of melatonin. The present study concludes that the anti-depressive effects of melatonin in LPS-induced depression might be mediated via autophagy modulation through FOXO3a signaling.
CONFLICT OF INTEREST
The authors declare no competing financial interests.
Supporting Information
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| jpi12667-sup-0001-FigS1.docxWord document, 122.2 KB | Fig S1 |
| jpi12667-sup-0002-FigS2.docxWord document, 13.6 MB | Fig S2 |
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| jpi12667-sup-0004-FigS4.docxWord document, 9.7 MB | Fig S4 |
| jpi12667-sup-0005-FigS5.docxWord document, 306.9 KB | Fig S5 |
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| jpi12667-sup-0010-AppendixS1.docxWord document, 20.6 KB | Appendix S1 |
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