Diallyl sulfide alleviates cisplatin-induced nephrotoxicity in rats via suppressing NF-κB downstream inflammatory proteins and p53/Puma signalling pathway

Abstract

Despite being a potent anticancer drug, nephrotoxicity is an adverse effect which renders the clinical use of cisplatin (Cis) limited. The protective role of diallyl sulfide (DAS); a naturally occurring organo-sulfide, present in garlic, in cisplatin-induced nephrotoxicity has been reported earlier. However, the mechanism through which DAS exerts its nephroprotective activity remains elusive. The aim of the current study was to elucidate the possible mechanisms underlying the reno-protective effect of DAS in cisplatin-induced nephrotoxicity in rats. DAS was given at 2 dose levels; 50 and 100 mg/kg, orally for 4 consecutive days, starting 1 hour after administration of single dose of cisplatin (3.5 mg/kg, intraperitoneally [i.p.]). The Cis-induced elevation in serum urea and creatinine, degree of histopathological alterations was significantly ameliorated in cisplatin groups co-treated with DAS. In addition, DAS significantly restored Cis-depleted glutathione (GSH) content and superoxide dismutase (SOD) activity and attenuated Cis-elevated Malondialdehyde (MDA) level. Also, DAS significantly reduced Cis-increased renal expression of nuclear factor kappa B (NF-κB) and subsequent pro-inflammatory mediators; tumour necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in kidney tissues. Moreover, co-treatment with DAS significantly inhibited Cis-increased caspase-8 and -9 levels. Additionally, DAS significantly mitigated Cis-induced protein expression of p53, Puma, and Bax while, it significantly restored Cis-reduced protein expression of Bcl-xL compared to the Cis group. In conclusion, these results demonstrate that DAS ameliorates cisplatin-induced nephrotoxicity in rats through enhancement of antioxidant defense, reduction of inflammatory cytokine tissue levels as well as inhibition of apoptosis via p53/Puma signalling pathway.

Keywords: NF-κB; cisplatin (Cis); diallyl sulfide; nephrotoxicity; p53.