Vincamine as an agonist of G-protein-coupled receptor 40 effectively ameliorates diabetic peripheral neuropathy in mice  

作　　者：Jia-wen Xu Xu Xu Yun Ling Yan-chun Wang Yu-jie Huang Juan-zhen Yang Jia-ying Wang Xu Shen 

机构地区：[1]Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases,Nanjing University of Chinese Medicine,Nanjing,210023,China [2]Department of Otolaryngology Head and Neck Surgery&Center of Sleep Medicine,Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,Shanghai,200233,China [3]National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture,Nanjing,210023,China

出　　处：《Acta Pharmacologica Sinica》2023年第12期2388-2403,共16页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(82273930);Innovative Research Team of Six Talent Peaks Project in Jiangsu Province(TD-SWYY-013);the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(No.2020YLXK018)and“Qing Lan”project.

摘　　要：Diabetic peripheral neuropathy(DPN)is a common complication of diabetes,which has yet no curable medication.Neuroinflammation and mitochondrial dysfunction are tightly linked to DPN pathology.G-protein-coupled receptor 40(GPR40)is predominantly expressed in pancreaticβ-cells,but also in spinal dorsal horn and dorsal root ganglion(DRG)neurons,regulating neuropathic pain.We previously have reported that vincamine(Vin),a monoterpenoid indole alkaloid extracted from Madagascar periwinkle,is a GPR40 agonist.In this study,we evaluated the therapeutic potential of Vin in ameliorating the DPN-like pathology in diabetic mice.Both STZ-induced type 1(T1DM)and db/db type 2 diabetic(T2DM)mice were used to establish late-stage DPN model(DPN mice),which were administered Vin(30 mg·kg-1·d-1,i.p.)for 4 weeks.We showed that Vin administration did not lower blood glucose levels,but significantly ameliorated neurological dysfunctions in DPN mice.Vin administration improved the blood flow velocities and blood perfusion areas of foot pads and sciatic nerve tissues in DPN mice.We demonstrated that Vin administration protected against sciatic nerve myelin sheath injury and ameliorated foot skin intraepidermal nerve fiber(IENF)density impairment in DPN mice.Moreover,Vin suppressed NLRP3 inflammasome activation through eitherβ-Arrestin2 orβ-Arrestin2/IκBα/NF-κB signaling,improved mitochondrial dysfunction through CaMKKβ/AMPK/SIRT1/PGC-1αsignaling and alleviated oxidative stress through Nrf2 signaling in the sciatic nerve tissues of DPN mice and LPS/ATP-treated RSC96 cells.All the above-mentioned beneficial effects of Vin were abolished by GPR40-specific knockdown in dorsal root ganglia and sciatic nerve tissues.Together,these results support that pharmacological activation of GPR40 as a promising therapeutic strategy for DPN and highlight the potential of Vin in the treatment of this disease.

关 键 词：diabetic peripheral neuropathy VINCAMINE GPR40 dorsal root ganglia sciatic nerve 

分 类 号：R965[医药卫生—药理学]