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

文献类型：期刊论文

作者Xu, Jia-wen3,4; Ma, Lin3; Xiang, Yu6; Dai, Meng-qing3; Li, Qiu-hui3; Jin, Xiao-yan6; Ruan, Yuan3; Li, Yang1,2; Wang, Jia-ying3; Shen, Xu3,5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-03-20
页码17
关键词diabetic peripheral neuropathy glabridin Kv2.1 dorsal root ganglia Schwann cells A beta/Kv2.1/NLRP3/p-Tau axis
ISSN号1671-4083
DOI10.1038/s41401-025-01526-6
英文摘要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 mu M. We showed that oral administration of GLA (30, 60 mgkg-1d-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 A beta and hyperphosphorylated tau proteins (p-Tau) were pathologically increased in serum of DPN patients. We demonstrated that Kv2.1 channels bridged A beta to activate NLRP3 inflammasome in Schwann cells and promote p-Tau production in DRG neurons through Schwann cells/DRG neurons crosstalk. GLA interrupted A beta/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.
WOS关键词DIABETIC PERIPHERAL NEUROPATHY ; MAJOR ACTIVE ISOFLAVAN ; NLRP3 INFLAMMASOME ; MITOCHONDRIAL DYSFUNCTION ; ACTIVATION ; ROOT ; LICORICE ; STREPTOZOTOCIN ; IMPAIRMENT ; APOPTOSIS
资助项目National Natural Science Foundation of China[82473982] ; National Natural Science Foundation of China[82273930] ; National Natural Science Foundation of China[32373005] ; Major Program of the Natural Science Foundation of the Jiangsu Higher Education Institutions of China[23KJA350002] ; Innovation Projects of State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical[NZYSKL240110] ; Shanghai Municipal Science and Technology Major Project[184319071000] ; Shanghai Municipal Science and Technology Major Project[19140903102] ; Qing Lan project ; Nantong Municipal Health Commission[MS2024024]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001448449600001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/316704]  
专题新药研究国家重点实验室
通讯作者Li, Yang; Wang, Jia-ying; Shen, Xu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Fudan Univ, Huashan Hosp, Natl Clin Res Ctr Aging & Med, Shanghai 200040, Peoples R China
3.Nanjing Univ Chinese Med, Sch Med, Nanjing 210023, Peoples R China
4.Nantong Univ, Med Sch Nantong Univ, Affiliated Hosp 2, Nantong Peoples Hosp 1, Nantong 226000, Peoples R China
5.Nanjing Univ Chinese Med, State Key Lab Technol Chinese Med Pharmaceut Proc, Nanjing 210023, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Jia-wen,Ma, Lin,Xiang, Yu,et al. Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway[J]. ACTA PHARMACOLOGICA SINICA,2025:17.
APA Xu, Jia-wen.,Ma, Lin.,Xiang, Yu.,Dai, Meng-qing.,Li, Qiu-hui.,...&Shen, Xu.(2025).Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway.ACTA PHARMACOLOGICA SINICA,17.
MLA Xu, Jia-wen,et al."Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway".ACTA PHARMACOLOGICA SINICA (2025):17.

入库方式： OAI收割

来源：上海药物研究所

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