Liraglutide activates autophagyviaGLP-1R to improve functional recovery after spinal cord injury

// Jian Chen 1, 2, * , Zhouguang Wang 2, * , Yuqin Mao 2, * , Zengming Zheng 1, 2 , Yu Chen 1 , Sinan Khor 3 , Kesi Shi 1 , Zili He 1 , Jiawei Li 1 , Fanghua Gong 2 , Yanlong Liu 2 , Aiping Hu 2 , Jian Xiao 1, 2 and Xiangyang Wang 1 1 Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China 2 Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China 3 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, U.S.A * These authors have contributed equally to this work Correspondence to: Jian Xiao, email: xfxj2000@126.com Xiangyang Wang, email: xiangyangwang@126.com Keyword: spinal cord injury, apoptosis, liraglutide, GLP-1R, autophagy Received: May 26, 2017     Accepted: July 13, 2017     Published: September 08, 2017 ABSTRACT 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 H 2 O 2 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.