title: Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats.
abstract: Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin.
authors.affiliation: Department of Pharmacology, National Organization for Drug Control and Research (NODCAR), Giza, Egypt.
authors.forename: Ali
authors.initials: A
authors.lastname: Khames
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt. Electronic address: marwa_mak@yahoo.com.
authors.forename: Marwa M
authors.initials: MM
authors.lastname: Khalaf
authors.affiliation: Department of Pharmacology, National Organization for Drug Control and Research (NODCAR), Giza, Egypt.
authors.forename: Amany M
authors.initials: AM
authors.lastname: Gad
authors.affiliation: Department of Pharmacology, National Organization for Drug Control and Research (NODCAR), Giza, Egypt.
authors.forename: Ola M
authors.initials: OM
authors.lastname: Abd El-Raouf
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection / Q000187:drug effects*; D004317:Doxorubicin / Q000009:adverse effects*; D004347:Drug Interactions; D000069465:Febuxostat / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014508:Urea / Q000097:blood; D014527:Uric Acid / Q000097:blood
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000069465:Febuxostat; D014527:Uric Acid; D008315:Malondialdehyde; D004317:Doxorubicin; D014508:Urea; D003404:Creatinine; D000068677:Sildenafil Citrate; D053148:Caspase 3; D005978:Glutathione
keywords: (PubChem CID: 31703); Adriamycin; Antiinflammatory; Doxorubicin; Febuxostat; Febuxostat (PubChem CID: 134018); Nephrotoxicity; Oxidative stress; Sildenafil; Sildenafil citrate (PubChem CID: 62853)