Sitagliptin improves functional recovery via GLP-1R-induced anti-apoptosis and facilitation of axonal regeneration after spinal cord injury
Sitagliptin improves functional recovery via GLP-1R-induced anti-apoptosis and facilitation of axonal regeneration after spinal cord injury
复制标题
西他列汀通过 GLP-1R 诱导的抗细胞凋亡和促进脊髓损伤后轴突再生来改善功能恢复
DOI：
10.1111/jcmm.15501
复制
发表时间：
2020-06-22
影响因子：
5.3
通讯作者：
Xiao, Jian
中科院分区：
文献类型：
--
作者：
Han, Wen;Li, Yao;Xiao, Jian
轴突生长和神经元凋亡被认为是针对脊髓损伤（SCI）的至关重要的治疗靶标。增长的证据报道刺激胰高血糖素样肽-1（GLP-1）/GLP-1受体（GLP-1R）信号传导轴可在神经变性疾病的实验模型中提供神经保护。内源性GLP-1被二肽基肽酶-IV（DPP4）迅速降解，导致GLP-1/GLP1R信号传导过程阻断。西格列汀是DPP4的高度选择性抑制剂，已批准对神经元受损的疾病产生有益的影响。然而，西他列汀在SCI修复中的作用和潜在机制尚不清楚。在这项研究中，我们使用了SCI和PC12细胞/原发性皮质神经元的大鼠模型来探索Sitagliptin Sci恢复的机制。我们发现SCI模型中GLP-1R的表达降低。 STAGLIPTIN的给药显着提高了GLP-1R蛋白水平，减轻了神经元凋亡，增强的轴突再生以及SCI后的功能恢复改善。然而，GLP-1R抑制剂Exendin9-39的治疗显着逆转了锡拉列汀的保护作用。此外，我们检测到AMPK/PGC-1α信号通路通过刺激GLP-1R激活。综上所述，西他列汀可能是通过GLP-1R诱导的AMPK/ PGC-1 Alpha信号通路进行轴突再生和运动功能修复的潜在药物。
Axon growth and neuronal apoptosis are considered to be crucial therapeutic targets against spinal cord injury (SCI). Growing evidences have reported stimulation of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) signalling axis provides neuroprotection in experimental models of neurodegeneration disease. Endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP4), resulting in blocking of GLP-1/GLP1R signalling process. Sitagliptin, a highly selective inhibitor of DPP4, has approved to have beneficial effects on diseases in which neurons damaged. However, the roles and the underlying mechanisms of sitagliptin in SCI repairing remain unclear. In this study, we used a rat model of SCI and PC12 cells/primary cortical neurons to explore the mechanism of sitagliptin underlying SCI recovery. We discovered the expression of GLP-1R decreased in the SCI model. Administration of sitagliptin significantly increased GLP-1R protein level, alleviated neuronal apoptosis, enhanced axon regeneration and improved functional recovery following SCI. Nevertheless, treatment with exendin9-39, a GLP-1R inhibitor, remarkably reversed the protective effect of sitagliptin. Additionally, we detected the AMPK/PGC-1 alpha signalling pathway was activated by sitagliptin stimulating GLP-1R. Taken together, sitagliptin may be a potential agent for axon regrowth and locomotor functional repair via GLP-1R-induced AMPK/ PGC-1 alpha signalling pathway after SCI.