Liraglutide activates autophagy via GLP-1R to improve functional recovery after spinal cord injury
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Jian Chen1,2,*, Zhouguang Wang2,*, Yuqin Mao2,*, Zengming Zheng1,2, Yu Chen1, Sinan Khor3, Kesi Shi1, Zili He1, Jiawei Li1, Fanghua Gong2, Yanlong Liu2, Aiping Hu2, Jian Xiao1,2 and Xiangyang Wang1
1Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
2Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
3Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, U.S.A
*These authors have contributed equally to this work
Jian Xiao, email: [email protected]
Xiangyang Wang, email: [email protected]
Keyword: spinal cord injury, apoptosis, liraglutide, GLP-1R, autophagy
Received: May 26, 2017 Accepted: July 13, 2017 Published: September 08, 2017
Therapeutics used to treat central nervous system (CNS) injury are designed to promote axonal regeneration and inhibit cell death. Previous studies have shown that liraglutide exerts potent neuroprotective effects after brain injury. However, little is known if liraglutide treatment has neuroprotective effects after spinal cord injury (SCI). This study explores the neuroprotective effects of liraglutide and associated underlying mechanisms. Our results showed that liraglutide could improve recovery after injury by decreasing apoptosis as well as increasing microtubulin acetylation, and autophagy. Autophagy inhibition with 3-methyladenine (3-MA) partially reversed the preservation of spinal cord tissue and decreased microtubule acetylation and polymerization. Additionally, siRNA knockdown of GLP-1R suppressed autophagy and reversed mTOR inhibition induced by liraglutide in vitro, indicating that GLP-1R regulates autophagic flux. GLP-1R knockdown ameliorated the mTOR inhibition and autophagy induction seen with liraglutide treatment in PC12 cells under H2O2 stimulation. Taken together, our study demonstrated that liraglutide could reduce apoptosis, improve functional recovery, and increase microtubule acetylation via autophagy stimulation after SCI. GLP-1R was associated with both the induction of autophagy and suppression of apoptosis in neuronal cultures.
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