南京中医药大学沈旭团队报道了光甘草定作为一种选择性Kv2.1抑制剂，通过破坏Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau通路改善DPN病理。该研究于2025年3月20日发表于国际一流学术期刊《中国药理学报》杂志上。

在这项研究中，该团队研究了GLA对晚期DPN的有益作用及其潜在机制。通过对CHO-Kv2.1细胞的电生理记录，研究小组鉴定出GLA是一种新的Kv2.1选择性抑制剂，IC50值为2.07μM。该团队发现口服GLA (30, 60 mg·kg⁻¹·d⁻¹)4周可显著改善DPN小鼠的所有神经功能障碍和周围血管功能障碍。

此外，该研究组证明了GLA可改善DPN小鼠表皮内神经纤维（IENF）密度损伤和髓鞘损伤，促进DRG神经元的突起生长，减轻DRG神经元的凋亡。通过注射腺相关病毒AAV8-Kv2.1-RNAi(AAV8-Kv2.1)， GLA在kv2.1基因敲除的DPN小鼠DRG和坐骨神经组织中的所有有益作用均被剥夺。研究组发现DPN患者血清中Aβ和高磷酸化Tau蛋白（p-Tau）的水平在病理上升高。研究组证明了Kv2.1通道桥接Aβ激活雪旺细胞中的NLRP3炎性体，并通过雪旺细胞/DRG神经元串扰促进DRG神经元中p-Tau的产生。GLA阻断Aβ/Kv2.1/NLRP3/p-Tau轴，改善小鼠DPN样病理。他们的结果支持Kv2.1抑制是DPN的一种治疗策略，并强调了GLA治疗这种疾病的潜力。

据了解，糖尿病周围神经病变（DPN）是糖尿病常见的并发症。DPN发病机制复杂，目前临床治疗DPN的药物疗效有限，副作用严重。因此，寻找针对DPN的有效靶点和药物是一个巨大的挑战。光甘草定（GLA）是从甘草根中提取的一种天然的丙烯化异黄酮。它具有广泛的药理活性，包括抗炎、抗氧化、心血管保护、神经保护、肝保护、抗肥胖和抗糖尿病等作用。

附：英文原文

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

Author: Xu, Jia-wen, Ma, Lin, Xiang, Yu, Dai, Meng-qing, Li, Qiu-hui, Jin, Xiao-yan, Ruan, Yuan, Li, Yang, Wang, Jia-ying, Shen, Xu

Issue&Volume: 2025-03-20

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 2.07μM. We showed that oral administration of GLA (30, 60mg·kg1·d1) 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.

DOI: 10.1038/s41401-025-01526-6

Source: https://www.nature.com/articles/s41401-025-01526-6