Carbon Antioxidants to Prevent Diabetic Complications

描述(由申请人提供)：线粒体产生过多的超氧化物已被证明是高血糖损伤的各种途径的共同之处。例如，通过补充超氧化物歧化酶使超氧化物生产正常化，消除了晚期糖基化终产物、蛋白激酶C活性、山梨醇浓度和氨基己糖途径通量的增加。因此，人们建议补充抗氧化剂以阻断超氧化物的过量产生，对糖尿病的广泛并发症具有治疗价值，包括肾小球硬化、多灶性轴索变性、视网膜缺血等。同时对这两种天然抗氧化剂(维生素E、a-硫辛酸等)进行了大量的体外研究。和合成抗氧化剂(Ebselen、超氧化物歧化模拟物等)虽然已经证明了清除活性氧的能力，但使用补充天然抗氧化剂的临床研究远没有那么有说服力。既需要在高血糖条件下对细胞培养中的抗氧化剂进行额外的测试，也需要新的抗氧化剂分子催化清除超氧化物，而不仅仅是清除每个抗氧化剂分子中的一个超氧化物分子。最近，一类新的合成抗氧化剂被证明在预防由氧化应激增加引起的其他疾病的小鼠模型中非常有效。人们认为，这些新的抗氧化剂的有效性来自于良好的细胞分布和对超氧化物失活的催化机制。该项目将确定这类抗氧化剂的成员是否能够扩展他们之前的成功，在高血糖条件下提供细胞保护，并赋予它们在延缓链脲佐菌素诱导的大鼠糖尿病引起的微血管并发症方面的益处。这项拟议工作的意义在于开发了一种新的有效抗氧化剂，适用于减轻与糖尿病相关的虚弱并发症。由于预计到2010年，仅在美国就有超过1700万人受到糖尿病的影响，一种足够有效的抗氧化剂预防或大幅减少糖尿病引起的并发症的影响将对公众健康产生广泛的影响。

DESCRIPTION (provided by applicant): Overproduction of superoxide by mitochondria has been demonstrated to be common to various pathways of hypergylcemic damage. Normalizing superoxide production, by supplemental superoxide dismutase e.g., eliminates the increases in advanced glycation end-products, protein kinase C activity, sorbitol concentration, and hexosamine pathway flux. It has therefore been proposed that supplemental antioxidants which interrupt the overproduction of superoxide should have therapeutic value against a wide spectrum of diabetic complications, including glomerulosclerosis, multifocal axonal degeneration, retinal ischemia, etc. While copious in vitro studies on both natural antioxidants (Vitamin E, a-Lipoic Acid, etc.) and synthetic antioxidants (ebselen, supoeroxide dismutatse mimetics, etc.) have demonstrated the ability to scavenge reactive oxygen species, clinical studies using supplemental natural antioxidants are far less conclusive. There are needs for both additional testing of antioxidants in cell cultures under hyperglycemic conditions and new antioxidant molecules that catalytically remove superoxide rather than merely scavenge one superoxide molecule per antioxidant molecule. Recently, a new class of synthetic antioxidants has been shown to be exceedingly effective at preventing mortality in mouse models of other disorders arising from increased oxidative stress. It is believed that the effectiveness of these new antioxidants arises from both a favorable cellular distribution and a catalytic mechanism for the deactivation of superoxide. This project will determine whether members of this class of antioxidants can extend their previous successes to afford protection of cells during hyperglycemic conditions, as well as to confer their benefits for retarding the microvascular complications arising from streptozotocin-induced diabetes in rats. The significance of the proposed work lies in the development of a new class of potent antioxidants suitable for mitigating the debilitating complications associated with diabetes. As diabetes is expected to affect over 17 million people in the USA alone by 2010, the impact of a sufficiently potent antioxidant that prevents or drastically reduces the complications arising from diabetes would have a broad impact on public health.