The effect of N-acetylcysteine on inflammation and oxidative stress in cisplatin induced nephrotoxicity: A rat model

Abstract

Introduction Cisplatin is one of the most effective chemotherapeutic agents used for the treatment of solid tumors. Despite its antitumor activity, it is also known for serious side effects. Major side effects include nephrotoxicity, neurotoxicity, and myelosuppression, and among these, the most serious and dose-limiting side effect that limits its clinical use and anticancer activity is nephrotoxicity. Despite its toxic characteristics, it is still widely used thanks to its therapeutic efficacy considering its risk/benefit ratio [1]. While cisplatin interacts with many cell components, the main biological target of the drug is deoxyribonucleic acid (DNA) [2]. However, as proximal tubule cells are nondividing cells, the nephrotoxic effect is believed to occur via mechanisms other than DNA damage. While different mechanisms are suggested for the development of nephrotoxicity, the most commonly accepted and investigated mechanisms are apoptosis, oxidative stress, and inflammation [3]. As no approved treatment protocol or specific antidote to be used against possible toxic effects of cisplatin use currently exists [4], different toxicity-preventing strategies are being rigorously investigated today. Routine applications to prevent nephrotoxicity include creating forced diuresis using mannitol and furosemide, using hypertonic chlorine solutions, using alternative cisplatin regimens, avoiding combination with other nephrotoxic agents, and using it together with compounds thought to be able to prevent nephrotoxicity [5]. Background/Aim: Cisplatin is a highly effective chemotherapeutic agent used in the treatment of solid organ cancers. Besides its chemotherapeutic effectiveness, cisplatin administration is associated with numerous side effects. Of those, the most clinically significant and common effect is nephrotoxicity. Recent studies reported that oxidative stress and inflammation are probably the most important mechanisms that contribute to the nephrotoxicity. N-acetylcysteine (NAC) is an antioxidant and antiinflammatory agent. In the present study, the effects of NAC on cisplatin-induced nephrotoxicity were investigated. Materials and methods: Rats were divided into four groups each including eight rats: CONT, NAC-250, CP, and CP+NAC. Rats in experimental groups were treated intraperitoneally (i.p.) with a single dose of cisplatin (10 mg/kg body weight) and i.p. with NAC (250 mg/kg body weight) for three consecutive days. Nephrotoxicity was determined by plasma BUN and creatinine levels. In tissue samples, myeloperoxidase (MPO), nuclear factor-kappa B (NF-kB), high mobility group box-1 (HMGB-1), total oxidant status (TOS), and total antioxidant status (TAS) levels were measured. Kidneys were analyzed histopathologically as well. Results: It was revealed that cisplatin was not effective on MPO, HMGB-1 and NF-kB levels but did increase TOS levels and decrease TAS levels in tissue samples. Interestingly, NAC elevated MPO and HMGB-1 levels significantly. Nevertheless, NAC ameliorated histological and functional change...

Dibenzazepine Attenuates Against Cisplatin-Induced Nephrotoxicity in Rats: Involvement of NOTCH Pathway

“…Previous studies showed that the expression of inflammatory cytokines is elevated in the kidney after cisplatin injury (Miller et al, 2010). The levels of several pro-inflammatory cytokines, such as TNF-α and IL-1β, were found to be elevated in the urine of cisplatin-treated mice (Gao et al, 2019;Güntürk Quantitative image analysis for immunohistochemical staining expressed as area percent across 10 different fields for each rat section. Values are given as mean ± SD of six observations, a or b: Statistically significant from the control or the cisplatin group, respectively at p < 0.05 using ANOVA followed by Tukey-Kramer as a post-hoc test.…”

“…Previous studies showed that the expression of inflammatory cytokines is elevated in the kidney after cisplatin injury ( Miller et al, 2010 ). The levels of several pro-inflammatory cytokines, such as TNF-α and IL-1β, were found to be elevated in the urine of cisplatin-treated mice ( Gao et al, 2019 ; Güntürk et al, 2019 ; Iwakura et al, 2019 ; Michel and Menze, 2019 ; Soetikno et al, 2019 ). In this study, the cisplatin-treated group showed a marked increase in pro-inflammatory cytokines tissue levels; IL-1β and TNF-α.…”

“…These include the inhibition of macrophage and T cell infiltration, M1/M2 transition and cytokine expression ( Jiandong et al, 2009 ; Piggott et al, 2011 ; Hans et al, 2012 ). Indeed, the treatment with anti-inflammatory agents is a promising strategy in reducing cisplatin-induced renal dysfunction and decreasing the histological evidence of injury ( El-Naga, 2014 ; El-Naga and Mahran, 2016 ; Gao et al, 2019 ; Güntürk et al, 2019 ; Iwakura et al, 2019 ; Michel and Menze, 2019 ; Soetikno et al, 2019 ).…”

“…Remarkably, the oxidative stress is actively involved in the pathogenesis of cisplatin-induced acute renal injury and immensely drives to apoptotic cell death both in vitro ( Yang et al, 2019 ) and in vivo ( Badawy et al, 2019 ; Soetikno et al, 2019 ). Also, there are multiple suggestion about the involvement of pro-inflammatory cytokines in the pathogenesis of cisplatin-induced nephrotoxicity ( Gao et al, 2019 ; Güntürk et al, 2019 ; Iwakura et al, 2019 ; Michel and Menze, 2019 ; Soetikno et al, 2019 ). Indeed, searching for other pathways that may be engaged in the pathogenesis of cisplatin renal injury is required for finding new promising protective strategies against this deleterious effect.…”

Protective Effect of Shikimic Acid against Cisplatin-Induced Renal Injury: In Vitro and In Vivo Studies

“…Recent studies have clarified the complex and multiple mechanisms of cisplatin nephrotoxicity, among which oxidative stress was defined as the main pathway and the key to prevent cell death caused by cisplatin [63][64][65][66][67]. In this study, the intercellular ROS level in the cisplatin-treated group increased five-fold compared with that in the control group.…”