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

• 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
• 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

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(申请人提供)：拟议的研究将测试一种新的硫醇抗氧化剂N-乙酰半胱氨酸酰胺(NACA)的眼药水配方在预防和治疗相关动物模型的白内障和视网膜退化方面的有效性。该应用程序的广泛、长期目标是开发用于治疗年龄相关眼病(AREDS)的NACA滴眼液配方，并推动更多地探索治疗各种年龄相关疾病的药理抗氧化方法。氧化应激损伤在AREDS发病机制中的重要性已经在白内障和干性形式的老年性黄斑变性(AMD)中得到证实。晶状体和黄斑都承受着显著的光氧化压力，而黄斑是新陈代谢活动和多不饱和脂肪浓度较高的地方。晶状体和视网膜细胞通过产生足够的抗氧化酶或小分子抗氧化剂，如谷胱甘肽(GSH)来对抗氧化应激。他们产生这种抗氧化剂的能力随着年龄的增长而下降，导致氧化损伤增加。在晶状体中，结果是晶体蛋白质的溶解度逐渐降低，表现为TE晶状体的混浊。在视网膜中，它会导致线粒体损伤和干性AMD的特征--干性黄斑变性。N-乙酰半胱氨酸(NAC)等抗氧化剂在改善氧化应激损伤方面表现出了良好的前景。我们的数据表明，作为一种稳定的NAC类似物，NACA在减少氧化应激方面比NAC起到了更好的作用。初步的动物研究表明，腹腔内应用NACA可减少白内障的形成，而将NACA应用于视网膜上皮细胞可防止细胞活力的丧失。建议的具体目标 研究旨在评估1)注射亚硒酸钠的雄性Wistar大鼠幼鼠的白内障形成情况，以及2)自发发生光感受器细胞早期(RD10+/+)或晚期(CCL2-/-)死亡的RD10+/+和CCL2-/-小鼠的视网膜变性。我们还将使用化学诱导的模型，在该模型中，将向C57/BL6小鼠注射碘酸钠以诱导RPE变性。NACA的保护作用将在动物模型中通过对不同实验组的白内障分期和测量混浊指数来评估，而在rd10+/+和CCL2-/-小鼠中，NACA的保护作用将通过测量外核层(ONL)密度和视杆细胞和视锥细胞视网膜电图(ERG)来测量视觉电位和光感受器功能来评估。在所有动物模型中，我们将通过去除目标组织(晶状体或视网膜)并测量一系列氧化应激参数、抗氧化酶活性以及促凋亡和凋亡蛋白(如细胞色素c和半胱氨酸天冬氨酸蛋白酶)的表达来评估NACA的抗氧化作用。我们还将研究晶体蛋白的蛋白质氧化、脂质过氧化以及蛋白质结合的GSH和半胱氨酸。 与公共卫生相关：与年龄相关的眼病导致的视力丧失目前影响着美国3000多万人--预计在未来几十年，这一数字将翻一番。白内障和老年性黄斑变性等疾病严重影响生活质量，并带来可观的医疗费用。在美国，每年用于白内障手术的总支出超过90亿美元，而与此类Visin问题相关的所有服务的总成本超过200亿美元。几项实验表明，一种名为N-乙酰半胱氨酸酰胺(NACA)的抗氧化剂可以延缓或阻止这些类型疾病的发病或进展。这项研究将在动物模型上测试滴眼剂形式的NACA是否可以预防和治疗白内障和黄斑变性等眼病。这项研究的成功结果将支持这种药物进入人类使用的进展。NACA眼药水将代表着昂贵的白内障手术的替代方案，降低与年龄相关的眼病相关的医疗保健成本，并极大地提高受这些疾病影响的人的生活质量。