الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
The present study aimed to examine the possible protective effects of benzbromaronethrough enhanced expression of PPAR-α(Fig 6.1), and amlodipine through GGT enzyme inhibition against cisplatin nephrotoxicity (Fig 6.2).The test drugs were given for normal as well as cisplatin-treated rats for 14 consecutive days. On the 10thday nephrotoxicity was induced by a single i.p. injection of cisplatin (6.5 mg/kg). Kidney functions wereassessed by measuring serum creatinine and BUN levels. Besides, renalGSH, MDA, NOx, and HO-1 contents, relative mRNA expressions of NADPH oxidase and Keap1, and relative protein expressions ofNrf2andHO-1were measured as oxidative stress biomarkers. While, renal TNF-αand IL-6 contents, and relative mRNA expressions of p38 MAPK, NF-κB p65, VCAM-1, and MCP-1were measured as indicators for inflammation. Moreover, renal HGF, and relativeprotein expressions ofBaxand Bcl-2were estimated as indicators for renal cell survival and apoptosis, respectively.The main findings of the present study can be summarized as follows:1.Cisplatinnephrotoxicity was associated with down-regulation of PPAR-α expression, enhanced oxidative stress, inflammatory response, and apoptosis.2.Cisplatinsignificantly increased GGT activity that initiates the metabolic conversion of cisplatin to a nephrotoxic thiol.3.Pretreatment with benzbromarone significantly enhanced PPAR-α expression in cisplatin treated rats, along with anti-oxidant, anti-inflammatory, and anti-apoptotic responses.
Summary and Conclusions1254.Pretreatment with amlodipine significantly inhibited GGT enzymein cisplatin treated ratsthat resulted in protection against oxidative stress by retarding GSH depletion due to the induced nephrotoxic thiol.5.Cisplatinsignificantlyincreased serum creatinine and BUN levels.Pretreatment with either benzbromarone or amlodipinesignificantly improved kidney functions as indicated by reduced serum creatinine and BUN levels. 6.Cisplatin nephrotoxicity was accompanied by oxidative stress, evidenced by an elevation of MDA, and a decline in GSH, NOx, and HO-1 contents, along with increased relative mRNA expressions of NADPH oxidase and Keap1, and decreased renal protein expressions ofNrf2and HO-1.7.Pretreatment with either benzbromarone or amlodipinesignificantly reduced MDA, and augmented GSH, NOx, and HO-1 contents, while decreased relative mRNA expressions of NADPH oxidase and Keap1, and increased renal protein expressions ofNrf2andHO-1.8.Cisplatinevokedan acute inflammatory response, indicated by the increase ofrenalTNF-α, IL-6contents, and relative mRNA expressions of p38 MAPK, NF-κB p65, VCAM-1, and MCP-1.9.Prophylactic treatment with either benzbromarone or amlodipinesignificantly decreased renalTNF-αand IL-6contents, relative mRNA expressions of p38 MAPK, NF-κB p65, VCAM-1, and MCP-1, thus affording a great anti-inflammatory action against cisplatin nephrotoxicity.10.Cisplatin induced apoptotic cell death through up-regulatedproteinexpression of thepro-apoptotic effectorBax, decreased expression ofthe anti-apoptotic proteinBcl-2,and reduced the renal cell survival factor HGF.
Summary and Conclusions12611.Pretreatment with either benzbromarone or amlodipinesignificantly down-regulated renal protein expressionof Bax and increased thatofBcl-2, in addition toaugmented renal HGF content.12.Histopathological examination of kidney tissue of rats treated withcisplatin showed congested renal capsules, degenerated tubules with hyaline casts, and pockets of inter-tubular hemorrhage.13.Histopathological examination of kidney tissue of rats pretreated with eitherbenzbromarone or amlodipine showed a good protective effect compared with those in cisplatin group,that wasaccompanied by the appearance of some regenerated cells.from the previous findings it can be concluded that:1.Benzbromarone can attenuate the nephrotoxicity caused bycisplatin associated with enhanced PPAR-α expression.2.Inhibition of GGT enzyme, which is the key step responsible for all the deleterious effects of cisplatin, is the main nephroprotective mechanism conferred by amlodipine.3.Both benzbromarone and amlodipine possess a great anti-oxidant effect through augmenting Nrf2 and HO-1 protein expressions.4.Both benzbromarone and amlodipine suppress the inflammatory signaling pathway p38 MAPK/NF-κB p65, resulting in reduced TNF-α and IL-6.5.Both drugsprotect the kidney from apoptotic cell death by reducing Bax/Bcl-2 ratio, and amlodipine elevates the survival factor HGF in kidney.6.Accordingly, prophylactic treatment with either benzbromarone or amlodipine could be a novel and promising therapeutic strategy in attempting to control cisplatin nephrotoxicity.7.Further clinical studies are required to prove these findings.