Therapeutic Effect of a Novel Antioxidant on Degenerative Eye Disorders

新型抗氧化剂对退行性眼部疾病的治疗作用

基本信息

批准号：
8367557
负责人：
NURAN ERCAL
金额：
$ 37.88万
依托单位：
MISSOURI UNIVERSITY OF SCIENCE & TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8367557
关键词：
Acetylcysteine Affect Age Age related macular degeneration Age-Months Animal Model Animals Antioxidants Apoptosis Apoptotic Blindness C57BL/6 Mouse Caspase Cataract Cataract Extraction Cell Death Cell Survival Cells Cellular Stress Characteristics Chemotactic Factors Crystalline Lens Crystallins Cysteine Data Deposition Disease Drug Formulations Drusen Early treatment Effectiveness Electroretinography Enzymes Epithelial Cells Event Eye Eye diseases Eyedrops Functional disorder Glutathione Goals Health Care Costs Human Injection of therapeutic agent Lipid Peroxidation Macular degeneration Measurement Measures Mediating Medical Metabolic Mitochondria Modeling Molecular Weight Mus N-Acetylcysteinamide Nuclear Ophthalmology Out-Migrations Oxidative Stress PTEN gene Pathogenesis Pathology Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Photoreceptors Physiological Play Postpartum Period Prevention Protein Binding Proteins Publishing Quality of life Rattus Reactive Oxygen Species Research Retina Retinal Retinal Degeneration Retinitis Pigmentosa Role Selenite Senile Cataract Services Site Solubility Staging Study models Sulfhydryl Compounds Testing Therapeutic Therapeutic Effect Tissues United States Vertebrate Photoreceptors Visual Wistar Rats Work age related analog base combat cost cytochrome c density epithelial to mesenchymal transition improved in vivo Model indexing intraperitoneal lens macrophage macula male novel oxidation oxidative damage polyunsaturated fat prevent prophylactic protective effect pup research study sodium iodate stressor

项目摘要

DESCRIPTION (provided by applicant): The proposed research will test the effectiveness of an eye drop formulation of a new thiol antioxidant, N- acetylcysteine amide (NACA), in preventing and treating cataracts and retinal degeneration in relevant animal models. This application's broad, long-term objectives are to develop an eye drop formulation of NACA for treatment of age-related eye diseases (AREDs) and to provide impetus for greater exploration of pharmacologic antioxidant approaches to the treatment of a variety of age-related diseases. The importance of oxidative stress damage in the pathogenesis of AREDs has been established for cataracts and the dry form of age-related macular degeneration (AMD). The lens and macula are both subjected to significant photo-oxidative stress, while the macula is the site of high rate of metabolic activity and the presence of concentrations of polyunsaturated fats. Lens and retinal cells combat oxidative stress by generating sufficient antioxidant enzymes or small molecular weight antioxidants like glutathione (GSH). Their ability to produce such antioxidants decreases with age, leading to increased oxidative damage. In the lens, the result is a progressive reduction in solubility of crystalline proteins that manifests in an opacification of te lens. In the retina, it results in mitochondrial damage and the accumulation of drusen that characterizes dry AMD. Antioxidants like N- acetyl cysteine (NAC) have shown promise in ameliorating oxidative stress damage. Our data indicates that a stable pharmaceutical analogue of NAC, NACA works much better than NAC in reducing oxidative stress. Preliminary animal studies have shown that intraperitoneal NACA reduces cataract formation while application of NACA to retinal epithelial cells prevents loss of cell viability. The Specific Aims of the proposed research are to evaluate 1) cataract formation in male Wistar rat pups receiving selenite injections and 2) retinal degeneration in rd10+/+ and Ccl2-/- mice that spontaneously develop progressive photoreceptor cell death either early (rd10+/+) or later (Ccl2-/-). We will also use a chemically-induced model, in which sodium iodate will be injected into C57/BL6 mice to induce RPE degeneration. The protective effects of NACA will be assessed in animal models by staging cataracts and measuring opacity indices in various experimental groups, while in the rd10+/+ and Ccl2-/- mice the protective effects of NACA will be assessed by measuring the visual potential and photoreceptor function based on measurements of outer nuclear layer (ONL) density and rod and cone electroretinograms (ERGs). In all animal models, we will assess the antioxidant effects of NACA by removing the target tissue (lens or retina) and measuring a number of oxidative stress parameters, the activities of antioxidant enzymes, and the expression of pro-apoptotic and apoptotic proteins such as cytochrome c and caspases. We will also study protein oxidation of crystallins, lipid peroxidation, and protein bound GSH and cysteine. PUBLIC HEALTH RELEVANCE: The loss of vision from age-related eye diseases now affects over 30 million people in the United States-a number that is expected to double in the coming decades. Diseases such as cataracts and age-related macular degeneration significantly affect quality of life and represent sizable medical costs. The annual total outlay for cataract surgery each year in the U.S. is over $9 billion while the total costs of all services related to such visin problems is over $20 billion. Several experiments show that an antioxidant called N-acetylcysteine amide (NACA) may delay the onset or halt the progression of these types of diseases. This research will test whether NACA in eye drop form can prevent and treat eye diseases such as cataracts and macular degeneration in animal models. Successful results from this study will support the advance of this medication into human use. NACA eye drops would represent an alternative to costly cataract surgery, reduce health care costs related to age-related eye diseases and greatly improve the quality of life of people affected by these diseases.

描述（由申请人提供）：拟议的研究将测试新型硫醇抗氧化剂N-乙酰半胱氨酸酰胺（NACA）在相关动物模型中预防和治疗性白内障和视网膜变性方面的滴眼剂配方的有效性。该应用程序的广泛长期目标是开发NACA的眼滴剂，以治疗与年龄相关的眼部疾病（AREDS），并提供动力，以更大程度地探索药物抗氧化剂的方法来治疗各种年龄相关疾病。氧化应激损伤在ARED的发病机理中的重要性已经建立了白内障和与年龄相关的黄斑变性（AMD）的干燥形式。晶状体和黄斑都遭受明显的光氧化应激，而黄斑则是高代谢活性率和浓度多不饱和脂肪的部位。晶状体和视网膜细胞通过产生足够的抗氧化剂酶或小分子量抗氧化剂（如谷胱甘肽（GSH））来对抗氧化应激。它们产生此类抗氧化剂的能力随着年龄的增长而降低，从而导致氧化损伤增加。在晶状体中，结果是晶体蛋白的溶解度逐渐降低，表现在te镜头的不透明中。在视网膜中，它会导致线粒体损伤和表征干燥AMD的drusen的积累。 N-乙酰基半胱氨酸（NAC）等抗氧化剂在改善氧化应激损伤方面已显示出希望。我们的数据表明，NACA的NAC稳定药物类似物在减少氧化应激方面的效果要比NAC好得多。初步动物研究表明，腹膜内NACA降低了白内障的形成，而NACA在视网膜上皮细胞中的应用可防止细胞活力的丧失。提议的具体目的研究是评估1）接受亚硒酸盐注射的男性Wistar大鼠幼崽中的白内障形成； 2）RD10+/+和CCL2 - / - 小鼠的视网膜变性，这些变性自发地发展了早期渐进的光感受器细胞死亡（RD10+/+）或以后（RD10+/+）或以后（CCL2-/ - / - /--/ - / - / - ）。我们还将使用化学诱导的模型，其中将碘酸钠注入C57/BL6小鼠中以诱导RPE变性。 NACA的保护作用将在动物模型中通过分阶段进行分阶段和测量各个实验组的不透明度指数进行评估，而在RD10+/+和CCL2 - / - 小鼠中，NACA的保护作用将通过基于外在核层（ONL）和coneles的测量来评估NACA的保护作用。在所有动物模型中，我们将通过去除靶组织（镜头或视网膜）并测量许多氧化应激参数，抗氧化剂酶的活性以及促凋亡性和凋亡性蛋白的表达来评估NACA的抗氧化作用。我们还将研究结晶蛋白，脂质过氧化以及蛋白结合的GSH和半胱氨酸的蛋白质氧化。公共卫生相关性：与年龄相关的眼病失去视力现在会影响美国超过3000万人，预计未来几十年中将翻一番。白内障和与年龄相关的黄斑变性等疾病显着影响生活质量并代表相当大的医疗费用。美国每年白内障手术的年度总支出超过90亿美元，而与此类Visin问题有关的所有服务的总成本超过200亿美元。一些实验表明，一种称为N-乙酰半胱氨酸酰胺（NACA）的抗氧化剂可能会延迟或停止这些类型的疾病的发展。这项研究将测试眼滴形式的NACA是否可以预防和治疗动物模型中白内障和黄斑变性等眼部疾病。这项研究的成功结果将支持这种药物对人类使用的进步。 NACA眼滴代表了昂贵的白内障手术，降低与年龄有关的眼部疾病有关的医疗费用的替代方法，并大大改善了受这些疾病影响的人们的生活质量。