title: A nitric oxide-donor furoxan moiety improves the efficacy of edaravone against early renal dysfunction and injury evoked by ischemia/reperfusion.
abstract: Edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, EDV) is a free-radical scavenger reduces organ ischemic injury. Here we investigated whether the protective effects of EDV in renal ischemia/reperfusion (I/R) injury may be enhanced by an EDV derivative bearing a nitric oxide- (NO-) donor furoxan moiety (NO-EDV). Male Wistar rats were subjected to renal ischemia (45 minutes), followed by reperfusion (6 hours). Administration of either EDV (1.2-6-30 µmol/kg, i.v.) or NO-EDV (0.3-1.2-6 µmol/kg, i.v.) dose-dependently attenuated markers of renal dysfunction (serum urea and creatinine, creatinine clearance, urine flow, urinary N-acetyl-β-D-glucosaminidase, and neutrophil gelatinase-associated lipocalin/lipocalin-2). NO-EDV exerted protective effects in the dose-range 1.2-6 µmol/kg, while a higher dose (30 µmol/kg) was needed to obtain protection by EDV. Both EDV and NO-EDV modulated tissue markers of oxidative stress and lipid peroxidation. NO-EDV, but not EDV, activated endothelial NO synthase (NOS) and blunted I/R-induced upregulation of inducible NOS, secondary to modulation of Akt and NF-κB activation, respectively. Besides NO-EDV administration inhibited I/R-induced IL-1β, IL-18, IL-6, and TNF-α overproduction. Overall, these findings demonstrate that the NO-donor moiety contributes to the protection against early renal I/R injury and suggest that NO-donor EDV codrugs are worthy of additional study as innovative pharmacological tools.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chegaev
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Rogazzo
authors.affiliation: Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino, Via Nizza 52, 10126 Torino, Italy ; ININCA-CONICET, Buenos Aires, Argentina.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cutrin
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Elisa
authors.identifier: 0000-0002-4481-0756
authors.initials: E
authors.lastname: Benetti
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Massimo
authors.identifier: 0000-0001-8782-3496
authors.initials: M
authors.lastname: Collino
mesh_terms: D000117:Acetylglucosamine / Q000652:urine; D000209:Acute-Phase Proteins / Q000652:urine; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000652:urine; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D014508:Urea / Q000097:blood
chemical_list: D000209:Acute-Phase Proteins; D016166:Free Radical Scavengers; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011518:Proto-Oncogene Proteins; C010166:furoxans; D008315:Malondialdehyde; D014508:Urea; D003404:Creatinine; D051057:Proto-Oncogene Proteins c-akt; D000077553:Edaravone; D000983:Antipyrine; D000117:Acetylglucosamine
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