Effects of 101BHG-D01, a novel M receptor antagonism, on allergic rhinitis in animal models and its mechanism
Effects of 101BHG-D01, a novel M receptor antagonism, on allergic rhinitis in animal models and its mechanism
复制标题
DOI：
10.1016/j.ejphar.2023.175902
复制
发表时间：
2023-07-14
影响因子：
5
通讯作者：
Dai，Haibin
中科院分区：
文献类型：
--
作者：
Shen，Huijuan;Wei，Hao;Dai，Haibin
变应性鼻炎(AR)是一种以打喷嚏和鼻痒为主要症状的鼻黏膜疾病。虽然AR的治疗不断改善，但仍然缺乏有效的药物。关于抗胆碱能药物是否能有效、安全地缓解AR症状和减轻鼻黏膜炎症仍存在争议。在此，我们合成了101BHG-D01，这是一种主要针对M3受体的新型抗胆碱能药物，可能会减少其他抗胆碱能药物对心脏的不良反应。我们评价了101BHG-D01对AR的影响，并探讨了抗胆碱能治疗AR的潜在分子机制。我们发现101BHG-D01有效地缓解了AR症状，减少了炎性细胞的浸润，减弱了炎性因子(IL-4、IL-5、IL-13等)的表达。在各种AR动物模型中。此外，101BHG-D01还可减少IgE刺激的大鼠腹膜间皮细胞(RPMCs)肥大细胞的活化和组胺的释放。此外，101BHG-D01还可降低IL-13刺激的大鼠鼻上皮细胞和人鼻上皮细胞中MUC5AC的表达。此外，IL-13刺激显著增加JAK1和STAT6的磷酸化，这一作用可被101BHG-D01抑制。我们证实，101BHG-D01可减少鼻黏膜粘液分泌和炎症细胞浸润，这可能是通过减少JAK1-STAT6信号通路的激活而发生的，表明101BHG-D01是一种有效且安全的抗胆碱能药物。
Allergic rhinitis (AR) is a nasal mucosal disease with sneezing and nasal itching as the main symptoms. Although AR treatment continues to improve, there remains a lack of effective drugs. There are still controversies regarding whether anticholinergic drugs can effectively and safely relieve the symptoms of AR and reduce inflammation in the nasal mucosa. Here, we synthesized 101BHG-D01, which is a novel anticholinergic drug that mainly targets the M3 receptor and may reduce the adverse effects of other anticholinergic drugs on the heart. We evaluated the effects of 101BHG-D01 on AR and investigated the potential molecular mechanism of anticholinergic therapy for AR. We found that 101BHG-D01 effectively alleviated AR symptoms, reduced the infiltration of inflammatory cells and attenuated the expression of inflammatory factors (IL-4, IL-5, IL-13, etc.) in various AR animal models. In addition, 101BHG-D01 reduced the activation of mast cells and the release of histamine from rat peritoneal mesothelial cells (RPMCs) challenged by IgE. Moreover, 101BHG-D01 reduced the expression of MUC5AC in IL-13-challenged rat nasal epithelial cells (RNECs) and human nasal epithelial cells (HNEpCs). Furthermore, IL-13 stimulation significantly increased JAK1 and STAT6 phosphorylation, which was suppressed by 101BHG-D01. We demonstrated that 101BHG-D01 reduced mucus secretion and inflammatory cell infiltration in the nasal mucosa, which may occur through a reduction in activation of the JAK1-STAT6 signaling pathway, indicating that 101BHG-D01 is a potent and safe anticholinergic therapy for AR.