Commiphora molmol protects against methotrexate-induced nephrotoxicity by up-regulating Nrf2/ARE/HO-1 signaling

• Published in: Biomedicine & pharmacotherapy 2018-10, Vol.106, p.499-509
• Main Authors: Mahmoud, Ayman M., Germoush, Mousa O., Al-Anazi, Khalid M., Mahmoud, Ahmed H., Farah, Mohammad Abul, Allam, Ahmed A.
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - enzymology; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; Animals; Anti-Inflammatory Agents - isolation & purification; Anti-Inflammatory Agents - pharmacology; Antioxidant Response Elements; Commiphora - chemistry; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers - isolation & purification; Free Radical Scavengers - pharmacology; Gene Expression Regulation, Enzymologic; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase (Decyclizing) - metabolism; Inflammation; Inflammation Mediators - metabolism; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Lipid Peroxidation - drug effects; Male; Methotrexate; Myrrh; Nephrotoxicity; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative stress; Oxidative Stress - drug effects; Phytotherapy; Plants, Medicinal; Rats, Wistar; Resins, Plant - isolation & purification; Resins, Plant - pharmacology; Signal Transduction - drug effects
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.06.171

[Display omitted] •Methotrexate induces oxidative stress, inflammation and kidney injury.•Myrrh scavenges free radicals in vitro and in vivo.•Myrrh up-regulates Nrf2/ARE/HO-1 signaling and prevents methotrexate nephrotoxicity. Commiphora molmol possesses multiple therapeutic benefits against various diseases; however, its protective role against methotrexate (MTX) renal toxicity has not been previously investigated. MTX is a dihydrofolate reductase inhibitor that can induce acute kidney injury (AKI). This study evaluated the in vitro antioxidant activity and the protective effect of C. molmol resin extract against MTX-induced oxidative stress, inflammation and renal injury. Male Wistar rats received 125 and 250 mg/kg C. molmol resin extract for 15 days and a single injection of MTX at day 16. C. molmol showed a radical scavenging activity against DPPH, superoxide and nitric oxide (NO) radicals. Rats received MTX showed renal injury evidenced by the significantly elevated serum creatinine and urea, and the histological alterations. The kidney of MTX-induced rats exhibited increased lipid peroxidation, NO, NF-κB and pro-inflammatory cytokines. Pre-treatment with C. molmol prevented MTX-induced kidney injury and attenuated oxidative stress and inflammation. C. molmol down-regulated Bax and enhanced the activity and expression of the antioxidant defenses. Furthermore, the expression of Bcl-2, Nrf2, NQO-1 and HO-1 was down-regulated in the kidney of MTX-induced rats. Pre-treatment with C. molmol resin up-regulated Bcl-2 and activated Nrf2/HO-1 signaling in the kidney of MTX-induced rats. In conclusion, C. molmol resin provided protection against MTX-induced AKI via activation of Nrf2 signaling and mitigation of oxidative stress.