2. Academic Validation
  3. Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway

Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway

  • Acta Pharmacol Sin. 2025 Mar 20. doi: 10.1038/s41401-025-01526-6.
Jia-Wen Xu # 1 2,  Lin Ma # 1,  Yu Xiang 3,  Meng-Qing Dai 1,  Qiu-Hui Li 1,  Xiao-Yan Jin 3,  Yuan Ruan 1,  Yang Li 4 5,  Jia-Ying Wang 6,  Xu Shen 7 8
Affiliations

Affiliations

  • 1 School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 2 Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong First People's Hospital, Medical School of Nantong University, Nantong, 226000, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. liyang@simm.ac.cn.
  • 5 National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China. liyang@simm.ac.cn.
  • 6 School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China. wangjy@njucm.edu.cn.
  • 7 School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China. xshen@njucm.edu.cn.
  • 8 State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, 210023, China. xshen@njucm.edu.cn.
  • # Contributed equally.
PMID: 40113986 DOI: 10.1038/s41401-025-01526-6
Abstract

Diabetic peripheral neuropathy (DPN) is a common diabetic complication. DPN has a complicated pathogenesis, and the currently clinical drugs against this disease show only limited efficacy and undesirable side effects. Thus, it is of great challenges to discover effective targets and drugs against DPN. Glabridin (GLA) is a natural prenylated isoflavone from the roots of Glycyrrhiza glabra. It exhibits a wide range of pharmacological activities including anti-inflammatory, antioxidant, cardiovascular protective, neuroprotective, hepatoprotective, anti-obesity and anti-diabetic effects, etc. In this study we investigated the beneficial effects of GLA on late-stage DPN and the underlying mechanisms. Using electrophysiological recording from CHO-Kv2.1 cells, we identified GLA as a new Kv2.1-selective inhibitor with an IC50 value of 2.07 μM. We showed that oral administration of GLA (30, 60 mg·kg-1·d-1) for 4 weeks significantly improved all neurological dysfunctions and peripheral vascular dysfunctions in DPN mice. Furthermore, we demonstrated that GLA administration improved intraepidermal nerve fiber (IENF) density damage and myelin sheath injury, promoted neurite outgrowth of DRG neurons and alleviated the Apoptosis of DRG neurons in DPN mice. All these beneficial effects of GLA were deprived in Kv2.1-knockdown DPN mice specifically in the DRG and sciatic nerve tissues by injection of adeno associated virus AAV8-Kv2.1-RNAi (AAV8-Kv2.1). We showed that the levels of Aβ and hyperphosphorylated tau proteins (p-Tau) were pathologically increased in serum of DPN patients. We demonstrated that Kv2.1 channels bridged Aβ to activate NLRP3 inflammasome in Schwann cells and promote p-Tau production in DRG neurons through Schwann cells/DRG neurons crosstalk. GLA interrupted Aβ/Kv2.1/NLRP3/p-Tau axis to ameliorate the DPN-like pathology in mice. Our results support that Kv2.1 inhibition is a therapeutic strategy for DPN and highlight the potential of GLA in treating this disease.

Keywords

Aβ/Kv2.1/NLRP3/p-Tau axis; Kv2.1; Schwann cells; diabetic peripheral neuropathy; dorsal root ganglia; glabridin.

Figures
Products