Vinpocetine attenuates 5-fluorouracil-induced intestinal injury: role of the Keap1/Nrf2/HO-1, NF-κB/TLR4/SOCS3 and RIPK1/RIPK3/MLKL signals

• Published in: Immunopharmacology and immunotoxicology 2024-12, Vol.46 (6), p.884-892
• Main Authors: Hassanein, Emad H M, Althagafy, Hanan S, Mansour, Sherif M A, Omar, Zainab M M, Hussein Hassanein, Mohamed Mahmoud, Abd El-Ghafar, Omnia A M
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - toxicity; Fluorouracil - adverse effects; Fluorouracil - pharmacology; Fluorouracil - toxicity; Heme Oxygenase (Decyclizing) - metabolism; Kelch-Like ECH-Associated Protein 1 - metabolism; Male; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Oxidative Stress - drug effects; Protein Kinases; Rats; Rats, Sprague-Dawley; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; Suppressor of Cytokine Signaling 3 Protein - metabolism; Toll-Like Receptor 4 - metabolism; Vinca Alkaloids - pharmacology
• ISSN: 0892-3973; 1532-2513; 1532-2513
• DOI: 10.1080/08923973.2024.2415111

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.