Effect of Combined Fenofibrate and Nicotinamide on Oxidative Stress and Inflammatory Cytokines Involved in Cisplatin-Induced Nephrotoxicity in Rats

Omaima M Abd Allah,Abeer A.I Sharaf El-Din,Fouad El Debakey

doi:10.3844/ajptsp.2014.206.222

Omaima M Abd Allah, Abeer A.I Sharaf El-Din + Show 1 more

Open Access

https://doi.org/10.3844/ajptsp.2014.206.222

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Abstract

Cisplatin (Cis) is an anticancer drug, which is accompanied with major side effects including nephrotoxicity. The current study was performed to assess the possible prophylactic effects of fenofibrate (FEN), Nicotinamide (NAM) and their combination on oxidative stress and inflammatory cytokines associated with cisplatin-induced renal damage. Rats were randomly divided into seven groups (8 each) as follows; control group; FEN group (100 mg/kg/day p.o.); NAM group (200 mg/kg/day p.o.); FEN and NAM were administered for eight days. Cis group (7 mg/kg i.p. as a single dose on day five); FEN + Cis group; NAM + Cis group and FEN + NAM + Cis group. Urine, blood and kidneys were taken out for biochemical and histopathological analysis and scoring. Oxidative stress induced by Cis was evidenced by significant elevation in renal Malondialdehyde (MDA) level acompanied by significant decrease in Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) in kidney tissues. Moreover, Cis produced significant increase in kidney Tumor Necrosis Factor-I± (TNF-I±) and Interleukin-6 (IL-6), the proinflammatory cytokines and significant decrease in Interleukin-10 (IL-10), the anti-inflammatory cytokine. However, administration of either FEN or NAM attenuated cisplatin-induced increased oxidative stress and inflammation in the kidney of rats, associated with improvement of the impaired renal function and histopathological changes, but their combination was found to be more effective in protection against cisplatin-induced renal damage than each drug alone. In conclusion, FEN and NAM combination protected the kidney tissue against cisplatin-induced nephrotoxicity through their antioxidant and anti-inflammatory activities.

Highlights

Nephrotoxicity is associate adverse effect of the anticancer drugs for solid and hematologic malignancies (Kintzel, 2001)
Administration of FEN and NAM in combination plus Cis resulted in significant (p
Cis-treated rats showed a pattern of extensive acute tubular necrosis, which included widespread degeneration of the tubular architecture, tubular dilatation, vacuolar degeneration, detachment and sloughing of epithelial cells from the basement membrane, intratubular cast formation and luminal congestion with extensive loss of the brush border

Summary

Introduction

Nephrotoxicity is associate adverse effect of the anticancer drugs for solid and hematologic malignancies (Kintzel, 2001). Cisplatinum or cisdiamminedichloroplatinum (II), a platinum-based drug, is one of the most frequently used anti-neoplastic agents. It has a potent anti-tumor action against wide range of malignancies, including testicular, ovarian, cervical, bladder and lung cancers as well as solid tumors resistant to other treatment regimens (Hanigan and Devarajan, 2003). Several strategies have been suggested to prevent this adverse effect, no specific treatments are currently recommended, except for vigorous hydration with normal saline (Launay-Vacher et al, 2008). New and effective therapeutic strategies are needed for prevention of cisplatin-induced nephrotoxicity. The production of nephrotoxic metabolites, vascular injury, inflammation, generation of free radicals and apoptotic pathways seem to play a crucial role (Pabla et al, 2009; Miller et al, 2010)

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