PHARMACOLOGICAL NEUROPROTECTION IN GLAUCOMA

青光眼的药理学神经保护

• 批准号: 6384719
• 负责人: ARTHUR H NEUFELD
• 金额: $ 41.51万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6384719
• 关键词: clinical research; disease /disorder prevention /control; drug design /synthesis /production; drug screening /evaluation; enzyme activity; enzyme inhibitors; eye disorder chemotherapy; eye pharmacology; glaucoma; human tissue; immunocytochemistry; in situ hybridization; intraocular pressure; isozymes; laboratory rat; molecular pathology; neural degeneration; neuroprotectants; nitric oxide synthase; optic nerve disorder; polymerase chain reaction; prostaglandin endoperoxide synthase; protein structure function; retinal ganglion

DESCRIPTION: Primary open-angle glaucoma and normal pressure glaucoma are sight threatening, age-related, eye disease that are often associated with intraocular pressure (IOP). Current treatments of the diseases are based on lowering the IOP, by pharmacological or surgical means, to prevent further degeneration of the optic nerve and loss of vision. Recent investigations on the cellular basis of neuronal degeneration in general, and the optic nerve in particular, have led to speculation that therapies directly aimed at preventing, slowing or reversing glaucomatous optic neuropathy can be developed. The long-term objective of this work is the identification of a class of compounds that could be developed as a pharmacological neuroprotective agents for the treatment of patients with glaucomatous optic neuropathy. Significant observations, made by this laboratory in human glaucomatous tissue, have described the presence of NOS-1, -1, -3, as well as COX-1 and -2, in the optic nerve head. Some of these pathways may contribute to neurodestruction in this tissue. The completion of the proposed specific aims: 1) identification of which isoforms of nitric oxide synthase (NOS) and cyclooxygenase (COX) pathways are upregulated or induced in human glaucomatous optic neuropathy, 2) demonstration of these specific pathways in the rat eye during optic nerve degeneration, and 3) study of the pharmacological inhibition of these specific pathways in a rat model of elevated IOP, will advance the development of the next generation of drugs to treat glaucoma. The proposed investigations are designed to first extend the observations in humans, by using immunohistochemistry, in situ hybridization, and reverse transcriptase-polymerase chain reaction, so that specific isoform pathways can be targeted for study in the rat. In the rat, optic nerve degeneration will be modeled using three approaches: chronic, moderately elevated IOP by three scleral vessel cautery, retinal ischemia by acute elevated IOP, and optic nerve transection. Specific pharmacological intervention will be tested in the rat model against NOS and COS isoform pathways that are identified in human glaucomatous tissue and potentially contributing to neurodestruction.

描述：主要的开角青光眼和正常压力青光眼是 视力威胁，与年龄有关的眼科疾病通常与 眼内压（IOP）。 当前的疾病治疗是基于 通过药理或外科手段降低IOP，以防止进一步 视神经的退化和视力丧失。 最近的调查 通常，在神经元变性的基础上，视神经 尤其是神经，导致人们猜测疗法直接针对 防止，减慢或逆转青光眼视神经神经病可以是 发达。 这项工作的长期目标是确定一类 可以作为药理神经保护性开发的化合物 用于治疗青光眼视力神经病患者的药物。 该实验室在人青光眼中进行的重大观察结果 组织描述了NOS -1，-1，-3以及Cox -1和Cox -1和 -2，在视神经头。 这些途径中的一些可能有助于 该组织中的神经污染。 拟议的特定的完成 目的：1）一氧化氮合酶（NOS）的同工型的鉴定 人类和环氧合酶（COX）途径在人类中被上调或诱导 青光眼视神经病变，2）这些特定途径的演示 在视神经变性过程中的大鼠眼中，3）研究 在大鼠模型中对这些特定途径的药理抑制 IOP提升，将推动下一代药物的发展 治疗青光眼。 拟议的调查旨在首先扩展观察结果 人类，通过使用免疫组织化学，原位杂交和反向 转录酶 - 聚合酶链反应，因此特定的同工型途径 可以针对大鼠研究。 在大鼠中，视神经变性 将使用三种方法对建模：慢性，中等升高的IOP 三个硬化容器捕捉，急性升高IOP的视网膜缺血，以及 视神经横向​​。 具体的药理干预将是 在大鼠模型中针对NOS和COS同工型途径进行测试 在人的青光眼组织中鉴定 神经造影。