Chiazza Fausto, Chegaev Konstantin, Rogazzo Mara, Cutrin Juan C, Benetti Elisa, Lazzarato Loretta, Fruttero Roberta, Collino Massimo
Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via P. Giuria 9, 10125 Torino, Italy.
Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino, Via Nizza 52, 10126 Torino, Italy ; ININCA-CONICET, Buenos Aires, Argentina.
Oxid Med Cell Longev. 2015;2015:804659. doi: 10.1155/2015/804659. Epub 2015 Mar 5.
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.
依达拉奉（5-甲基-2-苯基-2,4-二氢-3H-吡唑-3-酮，EDV）是一种自由基清除剂，可减轻器官缺血性损伤。在此，我们研究了携带一氧化氮（NO）供体呋咱部分的依达拉奉衍生物（NO-EDV）是否能增强依达拉奉对肾缺血/再灌注（I/R）损伤的保护作用。雄性Wistar大鼠经历肾缺血（45分钟），随后再灌注（6小时）。静脉注射依达拉奉（1.2 - 6 - 30 μmol/kg）或NO-EDV（0.3 - 1.2 - 6 μmol/kg）均能剂量依赖性地减轻肾功能障碍标志物（血清尿素和肌酐、肌酐清除率、尿流量、尿N-乙酰-β-D-葡萄糖苷酶以及中性粒细胞明胶酶相关脂质运载蛋白/脂质运载蛋白-2）。NO-EDV在1.2 - 6 μmol/kg剂量范围内发挥保护作用，而依达拉奉需要更高剂量（30 μmol/kg）才能获得保护。依达拉奉和NO-EDV均能调节氧化应激和脂质过氧化的组织标志物。NO-EDV而非依达拉奉激活了内皮型一氧化氮合酶（NOS），并分别通过调节Akt和NF-κB的激活，抑制了I/R诱导的诱导型NOS上调。此外，NO-EDV给药抑制了I/R诱导的IL-1β、IL-18、IL-6和TNF-α的过量产生。总体而言，这些发现表明NO供体部分有助于预防早期肾I/R损伤，并提示NO供体依达拉奉共药物作为创新的药理学工具值得进一步研究。
