南京中医药大学Xu Shen等研究人员合作发现，地氯雷他定可改善紫杉醇诱导的小鼠周围神经病变和超敏反应。2024年5月24日，国际知名学术期刊《中国药理学报》在线发表了这一成果。

紫杉醇（PTX）是治疗乳腺癌、肺癌、头颈部肿瘤和卵巢癌等多种实体瘤的主要化疗药物，具有严重的不良反应，包括PTX引起的周围神经病变（PIPN）和超敏反应（HSR）。推荐使用抗过敏药物苯海拉明（DIP）来缓解PTX引起的HSR。地氯雷他定（DLT）是第三代组胺H1受体拮抗剂，同时也是5HTR_2A的选择性拮抗剂。

研究人员探讨了DLT是否能改善小鼠的PIPN类症状及其内在机制。雄性小鼠通过注射PTX（4mg/kg，静脉注射）诱导PIPN，每隔一天注射一次，共注射4次。与对照组小鼠相比，小鼠的机械阈值、爪热反应潜伏期和爪冷反应潜伏期降低了50%。在建立PIPN小鼠模型阶段，每次给药PTX前30分钟用DLT（10mg/kg、20mg/kg，静脉注射）治疗PIPN小鼠，模型建立后每天给药4周。研究人员发现，DLT剂量依赖性地提高了PIPN小鼠的机械痛、热痛和冷痛阈值，而DIP（10mg/kg，静脉注射）对PIPN样症状没有改善作用。

研究人员发现，在PIPN小鼠活化的脊髓星形胶质细胞中，5HTR_2A的表达选择性升高。通过鞘内注射AAV9-5Htr2a-shRNA敲除脊髓特异性5HTR_2A能显著缓解PIPN小鼠的机械痛、冷热过敏症状，而服用DLT（20mg/kg）并不能进一步改善PIPN样症状。研究人员证实，服用DLT可减轻PIPN小鼠脊髓背根神经节神经元损伤，抑制坐骨神经破坏、脊髓神经元凋亡和神经炎症。此外，研究人员还发现，服用DLT可通过5HTR_2A/c-Fos/NLRP3通路抑制星形胶质细胞神经炎症，并通过靶向 5HTR_2A阻断星形胶质细胞-神经元交流。研究人员认为，脊髓5HTR_2A抑制有望成为PIPN的一种治疗方法，同时研究人员强调了DLT作为一种双功能药物，在化疗中改善PTX引起PIPN和HSR的潜力。

附：英文原文

Title: Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice

Author: Lu, Jian, Zhao, Xue-jian, Ruan, Yuan, Liu, Xiao-jing, Di, Xuan, Xu, Rui, Wang, Jia-ying, Qian, Min-yi, Jin, Hong-ming, Li, Wen-jun, Shen, Xu

Issue&Volume: 2024-05-24

Abstract: Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20mg/kg, i.p.) 30min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy.

DOI: 10.1038/s41401-024-01301-z

Source: https://www.nature.com/articles/s41401-024-01301-z