Liraglutide activates autophagy via GLP-1R to improve functional recovery after spinal cord injury.

Jian Chen,Zengming Zheng,Fanghua Gong,Aiping Hu,Sinan Khor,Jian Xiao,Yuqin Mao,Jiawei Li,Xiangyang Wang,Zili He,Kesi Shi,Zhouguang Wang,Yu Chen,Yanlong Liu

doi:10.18632/oncotarget.20791

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 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.

Highlights

Acute traumatic spinal cord injury (SCI) is a devastating disease that causes severe neurological deficits
Our study demonstrated that liraglutide could reduce apoptosis, improve functional recovery, and increase microtubule acetylation via autophagy stimulation after SCI
We explored whether mechanism by which liraglutide utilizes the GLP-1 receptor (GLP-1R) to regulate autophagy, mammalian target of rapamycin signaling, and apoptosis

Summary

Introduction

Acute traumatic spinal cord injury (SCI) is a devastating disease that causes severe neurological deficits. Neurons have highly polarized structures including one hair-like extension www.impactjournals.com/oncotarget that transmits signal (the axon) and several tapered, shorter extensions that receive signal (the dendrites) [7]. Cytoskeletal remodeling, such as the assembly of microtubules, is demonstrated to be pivotal for growth cone initiation and subsequent repair of injured axons [8, 9]. It was reported that epothilone B could reactivate polarization of neuronal structure via coordinated microtubule polymerization at the distal end of the axon, propelling axonal regeneration in an inhibitory environment [12]

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