Attenuation of p38 MAPK/NF-κB/TRPV1/CGRP is involved in the antinociceptive effect of hesperidin methyl chalcone and taxifolin in paclitaxel-induced peripheral neuropathy.

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY BioFactors Pub Date : 2024-10-01 DOI:10.1002/biof.2125
Wafaa S Abd Elaleem, Heba R Ghaiad, Mai A Abd Elmawla, Amira A Shaheen
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引用次数: 0

Abstract

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.

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紫杉醇诱导的周围神经病变中,橙皮甙甲基查尔酮和紫杉叶素的抗痛觉作用涉及 p38 MAPK/NF-κB/TRPV1/CGRP的减弱。
紫杉醇(PTX)诱发的周围神经病变(PIPN)是 PTX 的一种致残性副作用,对癌症患者的生活质量造成了不利影响。橙皮甙甲基查尔酮(HMC)和紫杉叶素(TAX)等黄酮类化合物具有抗炎、抗氧化、神经保护和抗痛觉作用,可减轻神经病理性疼痛。本研究旨在评估 HMC 和 TAX 单独或联合预防 PIPN 的功效。HMC 和 TAX 的预处理减轻了 PTX 引起的机械异感和痛觉减退、冷异感和热痛觉减退,并恢复了正常的组织学结构。值得注意的是,神经生长因子(NGF)、p38 丝裂原活化蛋白激酶(p38 MAPK)和瞬时受体电位类香草素 1 型(TRPV1)受到抑制,最终导致降钙素基因相关肽(CGRP)减少,从而缓解了神经性疼痛。此外,HMC 或 TAX 还能增强核因子红细胞 2 相关因子 2(Nrf2),从而提高谷胱甘肽(GSH)和总抗氧化能力(TAC),降低丙二醛(MDA),进而下调核因子卡巴 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-1β(IL-1β),进而降低细胞凋亡指数。令人欣慰的是,两种药物联合使用,通过靶向更多样化的信号通路,实现协同和综合治疗效果,优于单独使用每种药物。总之,HMC和TAX分别或联合预处理可通过调节NGF/p38 MAPK/NF-κB P65/TRPV1/CGRP 通路缓解PIPN。
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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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