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

Acta Pharmacologica Sinica volume 44, pages 2388–2403 (2023)Cite this article

Abstract

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 pancreatic β-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 either β-Arrestin2 or β-Arrestin2/IκBα/NF-κB signaling, improved mitochondrial dysfunction through CaMKKβ/AMPK/SIRT1/PGC-1α signaling 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.

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Fig. 1: Vin improved neurological dysfunctions in DPN mice through GPR40.
Fig. 2: Vin improved peripheral vascular dysfunctions through GPR40.
Fig. 3: Vin enhanced intraepidermal nerve fiber density and myelin sheath injury in DPN mice through GPR40.
Fig. 4: Vin alleviated inflammation in DPN mice involving GPR40/β-Arrestin2/NLRP3 pathway.
Fig. 5: Vin alleviated inflammation in DPN mice involving GPR40/β-Arrestin2/IκBα/NF-κB/NLRP3 pathway.
Fig. 6: Vin improved mitochondrial respiration impairments in DRG neurons from DPN mice through GPR40.
Fig. 7: Vin improved mitochondrial dysfunction of DPN mice through GPR40/CaMKKβ/AMPK/SIRT1/PGC-1α pathway.
Fig. 8: Vin improved oxidative stress through GPR40/Nrf2 pathway.

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Acknowledgements

This work was supported by 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. The authors thank Xia-lin Zhu (Central Hospital Affiliated to Shandong First Medical University) and Xiao-ju Xu (Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine) for expert technical assistance.

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  1. These authors contributed equally: Jia-wen Xu, Xu Xu

Authors and Affiliations

  1. Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Jia-wen Xu, Xu Xu, Yun Ling, Yan-chun Wang, Yu-jie Huang, Juan-zhen Yang, Jia-ying Wang & Xu Shen

  2. Department of Otolaryngology Head and Neck Surgery & Center of Sleep Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Xu Xu

  3. National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing, 210023, China

    Xu Shen

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Contributions

XS, JWX, and XX designed the study. XS reviewed the paper. JWX, XX, YL, YCW, YJH, and JZY performed the animal and cell experiments. JWX and XX analyzed interpreted data. JWX and JYW wrote the paper. XS, JWX, XX, YL, YCW, YJH, JZY, and JYW are the guarantors of this work and, as such, have full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the paper.

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Correspondence to Jia-ying Wang or Xu Shen.

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Xu, Jw., Xu, X., Ling, Y. et al. Vincamine as an agonist of G-protein-coupled receptor 40 effectively ameliorates diabetic peripheral neuropathy in mice. Acta Pharmacol Sin 44, 2388–2403 (2023). https://doi.org/10.1038/s41401-023-01135-1

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