紫杉醇（PTX）是针对乳腺癌、肺癌、头颈癌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 诱导的周围神经病变（PIPN）和过敏反应（HSR）。推荐的抗过敏剂苯海拉明 (DIP) 已被用于缓解 PTX 诱导的 HSR。 Desloratadine (DLT) 是第三代组胺 H1 受体拮抗剂，同时也是 5HTR2A 的选择性拮抗剂。在这项研究中，我们研究了 DLT 是否可以改善小鼠的 PIPN 样症状及其潜在机制。雄性小鼠通过每隔一天注射PTX（4mg/kg，腹腔注射）诱导PIPN，共4次。与对照小鼠相比，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 PTX 给药前 30 分钟用 DLT（10、20mg/kg，腹腔注射）处理 PIPN 小鼠，然后在模型建立后每天给药，持续 4 周。我们发现，DLT 给药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 给药（10mg/kg，腹腔注射）对 PIPN 样症状没有改善作用。我们发现 PIPN 小鼠活化的脊髓星形胶质细胞中 5HTR2A 的表达选择性升高。通过鞘内注射 AAV9-5Htr2a-shRNA 敲低脊髓特异性 5HTR2A 可显着减轻 PIPN 小鼠的机械痛觉过敏、热和冷超敏反应，而给予 DLT (20 mg/kg) 并不能进一步改善 PIPN 样症状。我们证明，DLT 给药可减轻 PIPN 小鼠的背根神经节神经元损伤，并抑制坐骨神经破坏、脊髓神经元凋亡和脊髓神经炎症。此外，我们发现 DLT 给药通过 5HTR2A/c-Fos/NLRP3 途径抑制星形胶质细胞神经炎症，并通过靶向 5HTR2A 阻断星形胶质细胞-神经元串扰。我们的结论是，脊髓 5HTR2A 抑制有望作为 PIPN 的治疗方法，并且我们强调 DLT 作为双功能药物在改善化疗中 PTX 诱导的 PIPN 和 HSR 方面的潜力。总之，我们确定脊髓 5HTR2A 在 PIPN 小鼠中被选择性激活，并且 DLT 可以改善 PTX 诱导的小鼠中 PIPN 和 HSR 样病理。 DLT减轻了PIPN小鼠DRG神经元和坐骨神经的损伤，同时抑制了脊髓神经元凋亡和CGRP释放。通过注射腺相关病毒 9 (AAV9)-5Htr2a-shRNA，对脊髓中 5HTR2A 特异性敲低的 PIPN 小鼠进行分析，深入研究了其潜在机制。 DLT 通过 5HTR2A/c-FOS 途径抑制星形细胞 NLRP3 炎性体激活介导的脊髓神经元损伤。我们的研究结果支持脊髓 5HTR2A 抑制显示出作为 PIPN 治疗策略的前景，并强调了 DLT 作为双功能药物在抗癌化疗中预防 PTX 诱导的 PIPN 和 HSR 效应的潜在优势。© 2024。作者（ s)，经中国科学院上海药物研究所和中国药理学会独家许可。

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 (4 mg/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, 20 mg/kg, i.p.) 30 min 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 (10 mg/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 (20 mg/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. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.