Liraglutide activates autophagy via GLP-1R to improve functional recovery after spinal cord injury.
Liraglutide activates autophagy via GLP-1R to improve functional recovery after spinal cord injury.
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DOI：
10.18632/oncotarget.20791
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发表时间：
2017-10-17
期刊：
影响因子：
--
通讯作者：
Wang X
中科院分区：
文献类型：
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作者：
Chen J;Wang Z;Mao Y;Zheng Z;Chen Y;Khor S;Shi K;He Z;Li J;Gong F;Liu Y;Hu A;Xiao J;Wang X
用于治疗中枢神经系统（CNS）损伤的治疗剂被设计为促进轴突再生和抑制细胞死亡。先前的研究表明，利拉鲁肽在脑损伤后发挥有效的神经保护作用。然而，对于利拉鲁肽治疗在脊髓损伤（SCI）后是否具有神经保护作用知之甚少。本研究探讨了利拉鲁肽的神经保护作用和相关的潜在机制。我们的研究结果表明，利拉鲁肽可以通过减少细胞凋亡以及增加微管蛋白乙酰化和自噬来改善损伤后的恢复。用3-甲基腺嘌呤（3-MA）抑制自噬部分逆转了脊髓组织的保存，并减少了微管乙酰化和聚合。此外，GLP-1 R的siRNA敲低在体外抑制了利拉鲁肽诱导的自噬并逆转了mTOR抑制，表明GLP-1 R调节自噬通量。GLP-1 R敲减改善了在H2 O2刺激下PC 12细胞中利拉鲁肽给药时观察到的mTOR抑制和自噬诱导。总之，我们的研究表明，利拉鲁肽可以减少细胞凋亡，改善功能恢复，并通过SCI后的自噬刺激增加微管乙酰化。GLP-1 R与神经元培养物中的自噬诱导和细胞凋亡抑制相关。
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.