Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats

Abstract

Methotrexate (MTX) is a cytotoxic chemotherapeutic agent used for treatment of several cancers. Nephrotoxicity, an adverse side effect of high-dose MTX, is attributed to abnormal production of reactive oxygen species (ROS), inflammatory mediators, and neutrophil infiltration. Montelukast (MON) is a cysteinyl leukotriene receptor antagonist. Recently, it has gained a considerable interest as a ROS scavenger and inflammatory modulator. In this study, we investigated the effect of MON against MTX-induced nephrotoxicity. Rats were divided into four groups: control group, MON group (10 mg/kg, orally), MTX group (20 mg/kg, i.p., single injection), and MON + MTX group (MON was administered 5 days before and 5 days after MTX administration). At the end of the experiment, serum was collected for analysis of blood urea nitrogen (BUN) and creatinine. Glutathione (GSH), lipid peroxides (malondialdehyde), tumor necrosis factor alpha (TNF-α) levels, superoxide dismutase, myeloperoxidase activities, and nuclear factor kappa beta (NF-κB) protein expression were determined in renal tissues. In addition, kidney tissues were examined histopathologically and immunohistochemically for NF-κB. MTX administration produced acute renal damage as indicated from severe elevation in BUN and serum creatinine. The role of oxidative stress and inflammatory mechanisms in MTX-induced nephrotoxicity was evidenced from the unbalance in tissue oxidative parameters, increased TNF-α levels, and NF-κB expression in renal tissues. On the other hand, MON significantly reduced the toxic effects of MTX as indicted from normalization of kidney-specific parameters, oxidative stress, and inflammatory mediators. This data was further supported by histopathological studies. Thus, co-administration of MON may be promising in alleviating the systemic side effects of MTX.

Significant curative functions of the mesenchymal stem cells on methotrexate‐induced kidney and liver injuries in rats

“…Several hypotheses have been suggested for the mechanisms underlying MTX toxicity, including the involvement of oxidative stress, inflammation, and apoptosis . MTX toxicity increases NOx in the tissues, leading to generation of peroxynitrite radicals that damage the cell . The oxidative stress which occurred by MTX administration in agreement with previous studies .…”

Effects of Lycopene Alone or Combined with Melatonin on Methotrexate-Induced Nephrotoxicity in Rats

“…It was reported that 20 mg/kg dose of Mtx, used in this study, highly exceeds interval dose and can be accepted as high dose Mtx in human (Oktem et al, 2006;Cetinkaya et al, 2007;Abdel-Raheem and Khedr, 2014). Mtx treatment at high doses may cause renal failure (Abelson et al, 1983).…”

Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties

“…TNF‐α, IL‐1β, IL‐6, and NF‐κB levels were assessed as markers of inflammation (Abdel‐Raheem & Khedr, ; Çakir et al, ; Elks et al, ). Their levels were significantly elevated ( p < .05) in the MTX‐treated animals compared to the control group.…”