Abstract
Objectives
Methotrexate (MTX) is an antimetabolite agent widely used to manage a variety of tumors and autoimmune diseases. Nonetheless, MTX-induced intestinal intoxication is a serious adverse effect limiting its clinical utility. Inflammation and oxidative stress are possible mechanisms for MTX-induced intestinal toxicity. Vinpocetine (VNP) is a derivative of the alkaloid vincamine with potent anti-inflammatory and antioxidant effects. The current study investigated the protective intestinal impact of VNP in attenuating MTX-induced intestinal intoxication in rats.
Materials and Methods
VNP was administered orally in a dose of 20 mg/kg, while MTX was injected intraperitoneal in a dose of 20 mg/kg.
Results
VNP administration attenuated drastic histological changes induced by MTX and preserved both normal villus and crypt histology. VNP significantly attenuated oxidative injury by upregulating intestinal Nrf2 and HO-1 expression. VNP attenuated inflammation by reducing MPO, NO2−, TNF-α, and IL-1β levels mediated by downregulating NF-κB, NDAPH-oxidase, IRF3, p-JAK-1, and p-STAT-3 expressions. Moreover, VNP potently counteracted intestinal necroptosis by effectively downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins.
Conclusion
Therefore, VNP may represent a promising approach that can attenuate intestinal toxicity in patients receiving MTX.
Acknowledgment
The authors gratefully acknowledge technical and financial support from the Ministry of Education and Deanship of Scientific Research (DSR), King Abdulaziz University (KAU), Deanship of Scientific Research (DSR), Jeddah, Saudi Arabia.
Disclosure statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. No potential conflict of interest was reported by the author(s).
Data availability statement
This article contains all of the data generated or evaluated throughout the study.