紫杉醇 (PTX) 引起的周围神经病变 (PIPN) 是 PTX 的一种致残副作用，会对癌症患者的生活质量产生不利影响。橙皮苷甲基查耳酮 (HMC) 和花旗松素 (TAX) 等黄酮类化合物可以通过其抗炎、抗氧化、神经保护和镇痛特性缓解神经性疼痛。目前的研究旨在评估 HMC 和 TAX 单独或联合使用预防 PIPN 的功效。 HMC 和 TAX 预处理可减轻 PTX 引起的机械异常性疼痛和痛觉过敏、冷异常性疼痛和热痛觉过敏，并恢复正常的组织学结构。值得注意的是，神经性疼痛通过抑制神经生长因子 (NGF)、p38 丝裂原激活蛋白激酶 (p38 MAPK) 和瞬时受体电位香草酸 1 型 (TRPV1) 得到缓解，最终导致降钙素基因相关肽减少。 CGRP）。此外，HMC 或 TAX 均可增强核因子红细胞 2 相关因子 2 (Nrf2)，导致谷胱甘肽 (GSH) 和总抗氧化能力 (TAC) 升高，同时丙二醛 (MDA) 降低，进而下调核因子 kappa B P65 (NF-κB P65) 及其磷酸化形式最终降低肿瘤坏死因子 α (TNF-α) 和白细胞介素 1 β (IL-1β)，从而降低细胞凋亡指数。令人鼓舞的是，两种药物的组合通过针对更多样化的信号通路并实现协同和全面的治疗效果，优于单独使用每种药物。总之，HMC 和 TAX 单独或联合预处理可通过调节 NGF/p38 MAPK/NF-κB P65/TRPV1/CGRP 通路缓解 PIPN。© 2024 国际生物化学与分子生物学联合会。

Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a disabling side effect of PTX, which adversely affects the life quality of cancer patients. Flavonoids such as hesperidin methyl chalcone (HMC) and taxifolin (TAX) can alleviate neuropathic pain via their anti-inflammatory, antioxidant, neuroprotective, and antinociceptive properties. The current study aimed to assess the efficacy of HMC and TAX in preventing PIPN individually or in combination. Pretreatment with HMC and TAX mitigated PTX-induced mechanical allodynia and hyperalgesia, cold allodynia, and thermal hyperalgesia as well as restore the normal histological architecture. Remarkably, neuropathic pain was relieved by suppression of nerve growth factor (NGF), p38 mitogen-activated protein kinase (p38 MAPK), and transient receptor potential vanilloid type-1 (TRPV1), which ultimately lead to reduced calcitonin gene-related peptide (CGRP). Furthermore, both HMC or TAX enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), leading to elevated glutathione (GSH) and total antioxidant capacity (TAC) along with lowered malondialdehyde (MDA), which in turn, downregulated nuclear factor kappa B P65 (NF-κB P65) and its phosphorylated form and eventually reduced tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) then lowered the apoptotic indices. Promisingly, the combination of both agents was superior to each drug alone through targeting more diverse signaling pathways and achieving synergistic and comprehensive therapeutic effects. In conclusion, pretreatment with HMC and TAX separately or in combination alleviated PIPN via modulating NGF/p38 MAPK/NF-κB P65/TRPV1/CGRP pathway.© 2024 International Union of Biochemistry and Molecular Biology.