Targeting inflammation and redox aberrations by perindopril attenuates methotrexate-induced intestinal injury in rats: Role of TLR4/NF-κB and c-Fos/c-Jun pro-inflammatory pathways and PPAR-γ/SIRT1 cytoprotective signals. (5th January 2022)

• Record Type: Journal Article
• Authors: Sayed, Ahmed M.; Abdel-Fattah, Maha M.; Arab, Hany H.; Mohamed, Wafaa R.; Hassanein, Emad H.M.
• Is Part Of: Chemico-biological interactions. Volume 351(2022)
• Publication Date: 2022-01-05
• Subjects: Methotrexate -- Intestinal injury -- Perindopril -- NF-κB -- c-Fos/c-Jun -- PPAR-γ/SIRT1; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2021.109732
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Aims: The use of methotrexate (MTX), a classical immunosuppressant and anti-cancer agent, is associated with multiple organ toxicities, including the intestinal injury. Components of the renin-angiotensin system are expressed in the intestinal epithelium and mucosal immune cells where they provoke pro-inflammatory and pro-oxidant action. The present study was conducted to investigate the potential ability of perindopril (PER), an angiotensin-converting enzyme inhibitor (ACEI), to attenuate MTX-induced intestinal injury with emphasis on the role of the pro-inflammatory TLR4/NF-κB and c-Fos/c-Jun pathways alongside PPAR-γ and SIRT1 cytoprotective signals. Materials and methods: The intestinal injury was induced by a single-dose injection of 20 mg/kg of MTX i.p at the end of the 5th day. PER was administrated once daily in a dose of 1 mg/kg, i.p, for five days before MTX and five days later. Results: Herein, perindopril attenuated the intestinal injury as seen by lowering the histopathological aberrations and preserving the goblet cells in villi/crypts. These beneficial actions were associated with downregulating the expression of the pro-inflammatory angiotensin II, TNF-α, IL-1β, and IL-6 cytokines, alongside upregulating the anti-inflammatory angiotensin (1–7) and IL-10. At the molecular level, perindopril downregulated the TLR4/NF-κB and c-Fos/c-Jun pathways in inflamed intestine of rats. Moreover, it attenuated the pro-oxidant events by lowering intestinal MDA and boosting GSH, SOD, and GST antioxidants together with PPAR-γ and SIRT1 cytoprotective signals. The aforementioned findings were also highlighted using molecular docking and network pharmacology analysis. Conclusions: Perindopril demonstrated notable mitigation of MTX-induced intestinal injury through suppression of TLR4/NF-κB and c-Fos/c-Jun pathways alongside the augmentation of PPAR-γ/SIRT1 cytoprotective signals. Graphical abstract: Image 1 Highlights: Perindopril attenuates methotrexate (MTX)-induced intestinal injury. It downregulates the Ang-II as well as TNF-α, IL-1β and IL-6 cytokines. It downregulates TLR4/NF-κB and c-Fos/c-Jun signaling. It counteracts oxidative stress and restores antioxidant status. It upregulates PPAR-γ and SIRT1 cytoprotective signals.