Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats

• Published in: Daru Vol. 27; no. 2; pp. 721 - 733
• Main Authors: Ebrahimi, Reihaneh, Sepand, Mohammad Reza, Seyednejad, Seyed Afshin, Omidi, Ameneh, Akbariani, Mostafa, Gholami, Maryam, Sabzevari, Omid
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2019
• Subjects: Administration, Oral; Animals; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; Ellagic Acid - administration & dosage; Ellagic Acid - pharmacology; Gene Expression Regulation - drug effects; Humans; Male; Malondialdehyde - metabolism; Medicinal Chemistry; Methotrexate - adverse effects; Mitochondria - drug effects; Mitochondria - metabolism; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - metabolism; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Rats; Rats, Wistar; Research Article; Up-Regulation; Oxidative stress; Inflammation; Mitochondrial dysfunction; Ellagic acid; Apoptosis
• ISSN: 2008-2231; 1560-8115; 2008-2231
• DOI: 10.1007/s40199-019-00309-9

Background The clinical application of methotrexate (MTX), an efficacious cytotoxic drug, is restricted due to its associated liver toxicity. Ellagic acid (EA), a natural polyphenol, possesses hepatoprotective, antioxidant and anti-inflammatory properties. Objectives The present study seeks to address the hepatoprotective effects of Ellagic acid (EA) against MTX-mediated oxidative stress (OS) and widen our current knowledge of the underlying molecular mechanisms of MTX toxicity. Methods Wistar rats were orally given EA (5 mg/kg and 10 mg/kg) for 10 successive days and at the end of the third day they were administered a single dose of MTX (20 mg/kg i.p). Results After performing biochemical analysis, liver enzymes and malondialdehyde were significantly higher in the MTX group, indicating hepatic oxidative damage. MTX-induced OS was further confirmed with observation of events such as reactive oxygen species (ROS) overproduction, mitochondrial outer membrane potential decrease, mitochondrial swelling, cytochrome c release and caspase-3/9 increase, resulting in apoptosis. Furthermore, overexpression of pro-inflammatory factors such as nuclear factor kappa B (NF-ĸB) and interleukin 6 (IL-6) indicated the MTX-induced inflammation in MTX-treated group. Interestingly, EA was able to significantly prevent OS, mitochondrial dysfunction, apoptosis and inflammation induced by MTX. Also, EA-treated rats demonstrated significant upregulation of both nuclear factor erythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1), which were considerably downregulated in MTX-treated rats. Conclusions EA protects rats against MTX-induced apoptosis and mitochondrial dysfunction via up-Regulating Nrf2 and HO-1 expression and inhibiting the NF-κB signaling pathway. Therefore, EA may protect patients against MTX-induced hepatotoxicity and encourage its clinical application. Graphical abstract Beneficial effect of Ellagic acid (EA) on Methotrexate (MTX)-induced liver injury: molecular mechanism.