Thalidomide Ameliorates Cisplatin-Induced Nephrotoxicity by Inhibiting Renal Inflammation in an Experimental Model

Abstract

Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

The effect of thalidomide on ethanol-induced gastric mucosal damage in mice: Involvement of inflammatory cytokines and nitric oxide

“…It has been shown that neutrophil 60 infiltration into the gastric mucosa has a critical role in the devel- suppress the production of TNF-a, IL-1b, IL-6 and NO in gastroin-89 testinal tissue [13][14][15][16]. In addition, our previous studies have also 90 confirmed that thalidomide exerts its anti-inflammatory effects by 91 suppressing the production of proinflammatory cytokines [17][18][19]. 92 TNF-a has a major role in the pathophysiology of ethanol-induced 93 gastric mucosal inflammation and damage [7,9,20].…”

“…190 2.9. Determination of malondialdehyde (MDA) levels 191The gastric tissue content of MDA was measured according to192 the thiobarbituric acid (TBA) method[19]. Briefly, 100 ll of the 193 supernatant was added to a reaction mixture containing 100 ll 194 of 20% (w/v) trichloroacetic acid (TCA) and 200 ll of…”

“…NO produced at site of inflamma-ONOO À ). Peroxynitrite is a cytotoxic oxidant that can cause cell 367 death by protein oxidation, lipid peroxidation, DNA damage and 368 inactivation of enzymes[19]. Lipid peroxidation following perox-369 ynitrite formation may be involved in the gastric mucosal injury 370[34].…”

Selenium protects cerebral cells by cisplatin induced neurotoxicity

“…Furthermore, experimental animal studies, focused on the role of antioxidants such as vitamin E, vitamin C, erythropoietin, thalidomide, melatonin, alpha lipoic acid, and fish oil, found out that these antioxidant agents are effective in cisplatin toxicities 15,31 .…”

Cisplatin-Induced Nephrotoxicity in Rats: Modulatory Role of Simvastatin and Rosuvastatin against Apoptosis and Inflammation

“…Significant elevation of myeloperoxidase (MPO) level in cisplatin nephrotoxicity has been observed along with pro-inflammatory cytokines; TNF-α, and IL-1β indicative of provoked inflammatory response as reported earlier (Amirshahrokhi and Khalili, 2015). Myeloperoxidase (MPO) was found to exert a primary role in chronic inflammation (Podrez et al, 2000) as well as in oxidative damage in various body organs (Vita et al, 2004) and demonstrates an essential mechanistic link between oxidation and inflammation (Madhusudhana Rao et al, 2011).…”