Zheng Jie, Gu Anqi, Kong Lingxuan, Lu Wenhan, Xia Jingsheng, Hu Huijuan, Hong Min
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Department of Pharmacology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
ACS Omega. 2024 Jan 31;9(6):7239-7248. doi: 10.1021/acsomega.3c09697. eCollection 2024 Feb 13.
: We previously found that cimifugin has a potent antiallergic inflammatory effect in atopic dermatitis (AD). However, whether cimifugin has an antipruritic effect in AD was unknown. : Mouse scratching behavior tests were performed to verify the proposed antipruritic effect of cimifugin on DNFB- or FITC-mediated AD. Chloroquine (CQ)- and compound 48/80-evoked acute itch models were employed to clarify the effect of cimifugin on histamine-dependent or -independent itch. Intracellular calcium changes were assessed in a primary culture of mouse dorsal root ganglia (DRG) in response to pruritogen exposure with or without cimifugin treatment, including CQ, histamine, allyl-isothiocyanate (AITC), and capsaicin. Molecular docking and microscale thermophoresis (MST) assays were performed to predict and verify the binding ability and modes between cimifugin and the CQ receptor MrgprA3, respectively. : We found that cimifugin attenuates itch behaviors effectively in FITC-induced AD. Notably, cimifugin significantly alleviated acute itching behaviors induced by CQ but not compound 48/80 in vivo. Moreover, cimifugin remarkably inhibited CQ-evoked calcium influx in DRG cells but had no obvious effect on histamine-induced calcium influx. Nevertheless, cimifugin did not interfere with either AITC-stimulated TRPA1 activation- or capsaicin-stimulated TRPV1 activation-mediated calcium influx in DRG cells. Molecular docking predicted that CQ and cimifugin might share similar binding abilities and binding modes with MrgprA3. MST assay confirmed cimifugin directly targeting MrgprA3. : The present study demonstrates that cimifugin has a potent antipruritic effect in AD with a histamine-independent mechanism via targeting the CQ receptor MrgprA3. Thus, cimifugin is a promising candidate antipruritic agent for AD.
我们之前发现升麻素在特应性皮炎（AD）中具有强大的抗过敏性炎症作用。然而，升麻素在AD中是否具有止痒作用尚不清楚。进行小鼠搔抓行为试验以验证升麻素对二硝基氟苯（DNFB）或异硫氰酸荧光素（FITC）介导的AD所提出的止痒作用。采用氯喹（CQ）和化合物48/80诱发的急性瘙痒模型来阐明升麻素对组胺依赖性或非依赖性瘙痒的作用。在小鼠背根神经节（DRG）原代培养物中，评估在有或没有升麻素处理的情况下，暴露于致痒原后细胞内钙的变化，致痒原包括CQ、组胺、烯丙基异硫氰酸酯（AITC）和辣椒素。分别进行分子对接和微量热泳动（MST）分析以预测和验证升麻素与CQ受体MrgprA3之间的结合能力和结合模式。我们发现升麻素能有效减轻FITC诱导的AD中的瘙痒行为。值得注意的是，在体内升麻素能显著减轻由CQ诱发的急性瘙痒行为，但对化合物48/80诱发的急性瘙痒行为无明显作用。此外，升麻素能显著抑制DRG细胞中CQ诱发的钙内流，但对组胺诱导的钙内流无明显影响。然而，升麻素并不干扰AITC刺激的TRPA1激活或辣椒素刺激的TRPV1激活介导的DRG细胞中的钙内流。分子对接预测CQ和升麻素可能与MrgprA3具有相似的结合能力和结合模式。MST分析证实升麻素直接靶向MrgprA3。本研究表明，升麻素通过靶向CQ受体MrgprA3在AD中具有强大的止痒作用，其机制不依赖组胺。因此，升麻素是一种有前景的AD止痒候选药物。
