PREVENTION & TREATMENT OF CISPLATIN- RHABDOMYOLYSIS- INDUCED NEPHROTOXICITY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 金属配合物防治顺铂-横纹肌溶解症肾毒性的研究 本提案的目的是合成，表征和测试几种新的金属（铜和锌）配合物的水杨酸和氨基硫醇衍生物作为催化抗氧化剂，抑制了广泛的活性氧（ROS）。这类化合物中的几种化合物已显示在人类疾病的体外和体内氧化应激模型中以多种方式有效。我们的初步数据强烈表明，这些金属配合物满足预防和治疗顺铂诱导的肾毒性（ROS介导的损伤）的许多标准，因为它们是活性，稳定和无毒的抗氧化剂。由于横纹肌溶解诱导的肾毒性也是ROS介导的，因此这些化合物也满足预防和治疗这种疾病引起的肾损伤的许多标准。我们假设，铜和锌的配合物可以合成，联合收割机的抗氧化剂配体的细胞保护作用与细胞恢复作用的必需金属，以保护肾小管上皮细胞的毒性，由于顺铂给药或横纹肌溶解症的发展。该提案有两个具体目标：具体目标1：合成，表征和评估几种铜和锌络合物的抗氧化性能。重点将放在配体上，这些配体具有或有助于细胞保护活性。我们将研究取代水杨酸盐和氨基硫醇类的配体。在我们的实验室中已经合成了几种这样的化合物，并在几种体外模型中显示出良好的活性。该特定目标将侧重于几种新化合物的化学研究，以及一些以前已知但尚未完全表征的化合物。所有新化合物将使用标准抗氧化剂测定法和循环伏安法测试抗氧化剂特性。具体目标2：评估金属络合物在体外和体内的肾保护活性。将使用体外培养的肾小管上皮细胞和小鼠模型，测试具有最高抗氧化活性的稳定水溶性化合物对顺铂和横纹肌溶解损伤的细胞保护作用。将进行实验以确定金属络合物对半胱天冬酶活化和半胱天冬酶依赖性或非依赖性内切核酸酶活化的影响。非常需要更好的药物来预防和治疗顺铂和横纹肌溶解诱导的肾毒性，以减少治疗相关的和共病的肾功能不全。在这项研究中提出的化合物的分子特征，联合收割机的抗氧化剂配体的细胞保护作用的细胞恢复作用的必需金属，锌，铜。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Prevention & Treatment of Cisplatin- Rhabdomyolysis- Induced Nephrotoxicity Using Metal Complexes The objective of this proposal is to synthesize, characterize, and test several new metal (copper and zinc) complexes of salicylic acid and aminothiol derivatives as catalytic antioxidants that scavenge a wide range of reactive oxygen species (ROS). Several compounds in this class have been shown to be efficacious in a variety of ways in in vitro and in vivo oxidative stress models of human diseases. Our preliminary data strongly indicate that these metal complexes satisfy many of the criteria for prevention and treatment of cisplatin-induced nephrotoxicity (an ROS-mediated injury), as they are active, stable, and nontoxic antioxidants. Since rhabdomyolysis-induced nephrotoxicity is also ROS-mediated, these compounds also satisfy many of the criteria for prevention and treatment of kidney injury due to this disease. We hypothesize that copper and zinc complexes can be synthesized that combine the cytoprotective effects of antioxidant ligands with the cytorecovery effects of the essential metals in order to protect kidney tubular epithelial cells from toxicity due to cisplatin administration or the development of rhabdomyolysis. The proposal has two specific aims: Specific Aim 1: Synthesize, characterize, and evaluate antioxidant properties of several copper and zinc complexes. The focus will be on ligands, which have or contribute to cytoprotective activity. We will examine ligands from the substituted salicylate and aminothiol classes. Several such compounds have been synthesized in our laboratory and have shown favorable activity in several in vitro models. This Specific Aim will focus on chemical studies of several new compounds, as well as some previously known but not fully characterized compounds. All new compounds will be tested for antioxidant properties using standard antioxidant assays and cyclic voltammetry. Specific Aim 2: Assess the nephroprotective activity of metal complexes in vitro and in vivo. The stable water-soluble compounds with the highest antioxidant activities will be tested for cytoprotection against cisplatin and rhabdomyolysis injuries using cultured tubular epithelial cells in vitro and in a mouse model. Experiments will be done to determine the effect of metal complexes on caspase activation and caspase-dependent or -independent endonuclease activation. Better agents for the prevention and treatment of cisplatin- and rhabdomyolysis-induced nephrotoxicities are greatly needed to reduce treatment-related and comorbid renal dysfunction. The compounds proposed in this study have molecular features that combine the cytoprotective effects of antioxidant ligands with the cytorecovery effects of the essential metals, zinc, and copper.