Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt.
Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia.
Immunopharmacol Immunotoxicol. 2024 Dec;46(6):884-892. doi: 10.1080/08923973.2024.2415111. Epub 2024 Oct 22.
5-Fluorouracil (5-FU) is a chemotherapy drug commonly prescribed in cancer management. Unfortunately, intestinal mucositis restricts 5-FU clinical use. Vinpocetine (VNP) is a synthetic alkaloid that is derived from vincamine. Our study was conducted to elucidate the intestinal protective effects of VNP on 5-FU intestinal injury in rats and explore the underlying mechanisms.
5-FU was injected i.p. for five days, while VNP was given P.O (5 and 10 mg/kg).
VNP effectively mitigates oxidative stress by a significant increase in GSH and SOD and decreasing MDA content mediated by Nrf2, HO-1 upregulation, and significant Keap1 downregulation. VNP mitigated inflammatory perturbations by decreasing MPO, TNF-α, IL-1β, and IL-6 facilitated by downregulating NF-κB and TLR4 and upregulating SOCS3 levels. In addition, the RIPK1, RIPK3, MLKL, and caspase-8 expression levels were significantly decreased, evidenced improvement of intestinal necroptosis by VNP.
Hence, VNP potently prevents intestinal injury induced by 5-FU by modulating Keap1/Nrf2/HO-1, NF-κB/TLR4/SOCS3, and RIPK1/RIPK3/MLKL signals.
氟尿嘧啶（5-FU）是一种常用于癌症治疗的化疗药物。不幸的是，肠黏膜炎限制了 5-FU 的临床应用。长春西汀（VNP）是一种从长春胺衍生而来的合成生物碱。我们的研究旨在阐明 VNP 对大鼠 5-FU 肠损伤的肠道保护作用，并探讨其潜在机制。
5-FU 腹腔注射五天，同时 VNP 口服（5 和 10mg/kg）。
VNP 通过增加 GSH 和 SOD 的表达，降低 MDA 含量，从而有效缓解氧化应激，这一过程由 Nrf2、HO-1 的上调和 Keap1 的下调介导。VNP 通过下调 NF-κB 和 TLR4 以及上调 SOCS3 水平，减少 MPO、TNF-α、IL-1β 和 IL-6，从而减轻炎症紊乱。此外，RIPK1、RIPK3、MLKL 和 caspase-8 的表达水平显著降低，表明 VNP 可改善肠道坏死性凋亡。
因此，VNP 通过调节 Keap1/Nrf2/HO-1、NF-κB/TLR4/SOCS3 和 RIPK1/RIPK3/MLKL 信号，有效预防 5-FU 诱导的肠道损伤。
