• Jingjing Ma, Min Shi, Xiangcheng Zhang, Xiaoning Liu, Juan Chen, Ridong Zhang, Xingzhou Wang, and Hong Zhang.
• Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China.
• Int. J. Mol. Med. 2018 May 1; 41 (5): 2977-2985.

AbstractThe present study aimed to investigate the mechanism of glucagon‑like peptide‑1 receptor (GLP‑1R) agonists in the progression of diabetic peripheral neuropathy (DPN) in streptozotocin (STZ)‑induced diabetic rats, through inflammatory signaling pathways. The DPN rat model was generated by intraperitoneal injection of STZ and then treated with the GLP‑1R agonist liraglutide or saline for 8 weeks. These animals were randomly divided into 4 groups (10 rats in each): The normal control + saline group, the normal control + liraglutide group, the diabetic + saline (DM) group and the diabetic + liraglutide (DML) group. The nerve conduction velocity (NCV) in the sciatic nerves of the rats was monitored over a period of 8 weeks. Peripheral serum was obtained for the measurement of blood glucose, tumor necrosis factor‑α (TNF‑α), interleukin‑6 (IL‑6) and IL‑1β level. The protein levels of phosphorylated (p‑) and total extracellular signal‑regulated kinase, c‑Jun NH2‑terminal kinases, p38 mitogen‑activated protein kinases (MAPK), and nuclear and cytoplasmic nuclear factor‑κB (NF‑κB) were measured through western blot analysis. Sciatic nerve mRNA expression levels of proinflammatory chemokines (TNF‑α, IL‑6 and IL‑1β), chemokines [monocyte chemoattractant protein‑1 (MCP‑1)], adhesion molecules [intercellular adhesion molecule 1 (ICAM‑1)], neurotrophic factors [neuritin, nerve growth factor (NGF) and neuron‑specific enolase (NSE)] and NADPH oxidase 4 (NOX4) were evaluated by reverse transcription-quantitative polymerase chain reaction. Subsequent to 8 weeks of treatment with liraglutide, the density of myelin nerve fibers was partially restored in the DML group. The delayed motor NCV and sensory NCV in the DML group were improved. The IOD value of NOX4 staining in the DML group (24.43±9.01) was reduced compared with that in the DM group (56.60±6.91). The levels of TNF‑α, IL‑1β and IL‑6 in the peripheral serum of the DML group were significantly suppressed compared with those of the DM group. It was also observed that the mRNA expression levels of TNF‑α, IL‑6, IL‑1β, MCP‑1, ICAM‑1 and NOX4 in the sciatic nerve were attenuated in the DML group. The mRNA expression of neuritin and NGF was significantly increased in the DML group compared with that of the DM group; NSE was reduced in the sciatic nerves of the DML group compared with that of the DM group. Additionally, the protein expression of p‑p38 MAPK and NF‑κB in the DML group was significantly suppressed. These data demonstrated that GLP‑1R agonists may prevent nerve dysfunction in the sciatic nerves of diabetic rats via p38 MAPK/NF‑κB signaling pathways independent of glycemic control. GLP‑1R agonists may be a useful therapeutic strategy for slowing the progression of DPN.

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