Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats

Abstract

Background:Intestinal toxicity is a serious side effect in methotrexate (MTX) chemotherapy.Objective:To investigate the mechanisms by which the anticancer drug MTX-induced intestinal damage could be prevented by thymoquinone (TQ), an active ingredient of Nigella sativa.Materials and Methods:TQ was given orally for 10 days, and MTX toxicity was induced at the end of day 3 of the experiment, with or without TQ pretreatment.Results:MTX caused intestinal damage, represented by distortion in normal intestinal histological structure, with significant oxidative stress, exhibited as decrease in reduced glutathione concentration and catalase activity, along with significant increase in malondialdehyde level compared to control group. MTX also caused nitrosative stress evident by increased intestinal nitric oxide (NO) level, with up-regulation of inducible NO synthase expression shown in immunohistochemical staining. Furthermore, MTX caused inflammatory effects as evident by up-regulation of intestinal necrosis factor-kappa beta and cyclooxygenase-2 expressions, which were confirmed by increased intestinal tumor necrosis factor-alpha level via enzyme-linked immunosorbent assay. Moreover, MTX caused apoptotic effect, as it up-regulated intestinal caspase 3 expression. Concomitant TQ significantly reversed the MTX-induced intestinal toxic effects by reversing intestinal microscopic damage, as well as significantly improving oxidative/nitrosative stress, inflammatory and apoptotic markers tested compared to MTX alone.Conclusion:TQ may possess beneficial intestinal protective effects as an adjuvant co-drug against MTX intestinal toxicity during cancer chemotherapy. TQ protection is conferred via antioxidant, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms.SUMMARY Methotrexate induces oxidative and nitrosative stress in intestinal tissuesMethotrexate also initiates inflammatory and apoptotic intestinal injuryThymoquinone co-administration ameliorates methotrexate-induced intestinal toxicityThymoquinone has antioxidative, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms. Abbreviations used: COX-2: Cyclooxygenase-2, ELISA: Enzyme-linked immunosorbent assay, H and E: Hematoxylin and eosin, iNOS: Inducible nitric oxide synthase, MDA: Malondialdehyde, MTX: Methotrexate, NO: Nitric oxide, NF-κB: Nuclear factor-κB, GSH: Reduced glutathione, TQ: Thymoquinone, TNF-α: Tumor necrosis factor-alpha

Human placental extract ameliorates methotrexate-induced hepatotoxicity in rats via regulating antioxidative and anti-inflammatory responses

“…Methotrexate (MTX)-induced hepatotoxicity is a serious problem, because it affects MTX’s clinical therapeutic effects. Oxidative stress and lipid peroxidation mediated by oxygen free radicals have been considered as an important cause of MTX-induced neurotoxicity [ 8 – 11 ], hepatotoxicity [ 13 , 14 ], intestinal toxicity [ 50 ], and nephrotoxicity [ 12 ]. The present study demonstrates the ability of human placenta extract (HPE) to ameliorate MTX-induced hepatotoxicity.…”

The Possible Contribution of P-Glycoprotein in the Protective Effect of Paeonol against Methotrexate-Induced Testicular Injury in Rats

“…Inhibition of dihydrofolate reductase by MTX results in suppression of purine and pyrimidine nucleotide production, and subsequently, inhibition of DNA and RNA synthesis, especially in rapidly dividing malignant cells [ 1 , 2 ]. Unfortunately, the cytotoxic effects of MTX are not limited to malignant cells but can also affect normal cells in different organs [ 3 , 4 , 5 ], including the testis [ 6 , 7 ]. Increased oxidative stress, inflammation, and apoptosis may also account for MTX-induced cellular damage [ 5 , 6 ].…”

Induction and Amelioration of Methotrexate-Induced Gastrointestinal Toxicity are Related to Immune Response and Gut Microbiota

“…This is due, at least in part, to the lack of understanding of the mechanisms by which MTX induces intestinal impairment. A limited number of studies suggest that the administration of MTX induces DNA strand breaks in rapidly proliferating intestinal epithelial cells [ 16 ] and causes significant oxidative stress [ 17 , 18 ]. More importantly, MTX may exert deleterious effects through a dynamic sequence of complex inflammatory events initiated by direct cellular injury in the intestinal epithelium and submucosal tissues [ 16 , 19 ].…”