Parthenolide reduces cisplatin-induced renal damage.
Inflammatory events contribute to cisplatin-induced renal damage. Cisplatin promotes increased production of reactive oxygen species, which can activate nuclear factor-kappaB (NF-kappaB) that lead to increased expression of proinflammatory mediators which could intensify the cytotoxic effects of cisplatin. In this study, we evaluated the effect of parthenolide, a selective inhibitor of NF-kappaB, on renal damage caused by cisplatin use. A total of 94 male Wistar rats were divided into six groups: Group A (18 rats) were treated with saline; Group B (12 rats) received dimethylsulfoxide plus saline (the solvent for parthenolide); Group C (12 rats) received parthenolide (3mg/kg) plus saline; Group D (20 rats) received cisplatin (5mg/kg, i.p.); Group E (12 rats) received dimethylsulfoxide plus cisplatin (5mg/kg, i.p.); and Group F (21 rats) received parthenolide (3mg/kg) plus cisplatin (5mg/kg, i.p.). Dimethylsulfoxide or parthenolide were administered at 24h and 1h prior to cisplatin injection, and again at 24h and 48h after. At 2, 3 and 5 days after saline or cisplatin injection, blood and urine samples were collected for measurement of creatinine, sodium and potassium and the kidneys removed for histological, morphometric, electrophoretic mobility shift assay (EMSA), apoptosis and immunohistochemical studies. Cisplatin-treated rats presented higher plasma creatinine, as well as greater immunostaining for ED1 (macrophages/monocytes) and NF-kappaB in the renal cortices and outer medullae. The increase of NF-kappaB activation was confirmed by EMSA. Cisplatin-injected rats also presented higher urinary levels of lipid peroxidation and acute tubular necrosis. All of these alterations were reduced by treatment with parthenolide. This effect seems to be related, at least in part, to the restriction of renal inflammatory process observed in parthenolide+cisplatin treated rats.
Francescato
Heloísa D C
HD
Department of Physiology, Faculty of Medicine of Ribeirão Preto, Ribeirão Preto Av Bandeirantes, 3900 CEP 14049-900, Ribeirão Preto, SP, Brazil.
Costa
Roberto S
RS
Scavone
Cristoforo
C
Coimbra
Terezila M
TM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D024202:Electrophoretic Mobility Shift Assay; D005919:Glomerular Filtration Rate; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D007679:Kidney Medulla / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008054:Lipid Peroxides / Q000652:urine; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D008054:Lipid Peroxides; D016328:NF-kappa B; D009687:Nuclear Proteins; D012717:Sesquiterpenes; D013481:Superoxides; C002669:parthenolide; D048031:JNK Mitogen-Activated Protein Kinases; D002945:Cisplatin