The protective role of luteolin against the methotrexate-induced hepato-renal toxicity via its antioxidative, anti-inflammatory, and anti-apoptotic effects in rats

Abstract

Methotrexate (MTX) is frequently used drug in treatment of cancer and autoimmune diseases. Unfortunately, MTX has many side effects including the hepato-renal toxicity. In this study, we hypothesized that Luteolin (Lut) exhibits protective effect against the MTX-induced hepato-renal toxicity. In order to investigate our hypothesis, the experiment was designed to examine the effect of exposure of male rats to MTX (20 mg/kg, i.p., at day 9) alone or together with Lut (50 mg/kg, oral for 14 days) compared to the control rats (received saline). The findings demonstrated that MTX treatment induced significant increases in the liver and kidney functions markers in serum samples including Aspartate transaminase (AST), Alanine transaminase (ALT), creatinine, urea and uric acid. MTX also mediated an oxidative stress expressed by elevated malondialdehyde (MDA) level and decreased level of reduced glutathione (GSH), antioxidant enzyme activities, and downregulation of the Nrf2 gene expression as an antioxidant trigger. Moreover, the inflammatory markers (NF-κB, TNF-α, and IL-1β) were significantly elevated upon MTX treatment. In addition, MTX showed an apoptotic response mediated by elevating the pro-apoptotic (Bax) and lowering the anti-apoptotic (Bcl-2) proteins. All of these changes were confirmed by the observed alterations in the histopathological examination of the hepatic and renal tissues. Lut exposure significantly reversed all the MTX-induced changes in the measured parameters suggesting its potential protective role against the MTX-induced toxicity. Finally, our findings concluded the antioxidative, anti-inflammatory and anti-apoptotic effects of Lut as a mechanism of its protective role against the MTX-induced hepato-renal toxicity in rats.

Renoprotective Influence of Pomegranate Juice on Nephrotoxicity Induced by Methotrexate

“…In addition, there was a significant rise in ionic K+ with a significant decline in serum ionic Na+. These results were in accordance with those obtained by Asvadi et al [37] and Gaies et al [38] who established current findings.…”

Protective effect of luteolin against chemical and natural toxicants by targeting NF‐κB pathway

“…LUT exposure significantly reversed the MTX‐induced apoptotic functions via diminishing the pro‐apoptotic (Bax) and elevating the antiapoptotic (Bcl‐2) proteins. Histopathological examinations of hepatic and renal tissue confirmed the biochemical findings 81 . LUT may have a protective role against MTX‐induced disturbances in hepatic and renal functions.…”

“…Unfortunately, MTX is associated with a variety of side effects, such as pneumonia, nephrotoxicity, and hepatotoxicity that can hinder its usefulness, often leading to discontinuation 82 . LUT has been reported to significantly reduce elevated AST, ALT, serum creatinine, urea, and uric acid in several experimental systems 81 . LUT was also reported to diminish the MTX‐mediated oxidative stress and restore the antioxidant levels such as GSH.…”

Protective Effect of Pycnogenol against Methotrexate-Induced Hepatic, Renal, and Cardiac Toxicity: An In Vivo Study

“…Continuous MTX administration showed cytotoxic effects that were not limited to cancer cells but extended to affect vital organs, including the heart [42]. MTX therapy induces oxidative stress and inflammatory pathways in non-target cells and subsequent tissue damage [43,44].…”