Effect of Isoprostanes on Retinal Transmitter Release

异前列烷对视网膜递质释放的影响

• 批准号: 6555984
• 负责人: CATHERINE A OPERE
• 金额: $ 14.25万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6555984
• 关键词: arachidonate; aspartate; catecholamines; cow; dopamine; gamma aminobutyrate; glutamates; high performance liquid chromatography; laboratory rabbit; neuroregulation; neurotransmitter transport; prostaglandins; radiotracer; retina; thromboxanes

DESCRIPTION (provided by applicant): Isoprostanes (IsoP's) are a series of prostaglandin-like compounds that are formed in abundance in vivo by a non-enzymatic, free radical catalyzed peroxidation of arachidonic acid independent of cyclooxygenase. In addition to providing a reliable measure of in vivo and in vitro oxidative stress, IsoP's can exert pharmacological effects in some tissues. A review of literature revealed that very few studies have addressed the effects of IsoP's on neurotransmitter release from central or peripheral tissues. Although IsoP's have been reported to modulate sympathetic neurotransmission from anterior uveal tissues, no studies have investigated the potential regulatory effects of these compounds on neurotransmission in the retina. In the present study, we will test the hypothesis that IsoP's can modulate glutamate, gamma-aminobutyric acid (GABA) and dopaminergic transmission in the retina both in vitro and in vivo. The overall objective of the present study is to examine the effect of different series of IsoP's (A1, E1, E2, F1, F2 and F3) on glutamate, GABA and dopamine release from retinae both in vitro and in vivo. Experiments in this project have, therefore, been designed to answer the following questions: (i) do different IsoP's alter the release and/or availability of glutamate, GABA and dopamine in vitro and in vivo? (ii) are the effects produced by IsoP's comparable to those of other arachidonic acid metabolites (prostaglandins and thromboxanes)? (iii) what is the role of presynaptic IsoP heteroreceptors in the effects caused by these compounds on glutamate, GABA and dopamine in vitro and in vivo? We anticipate that the results of the present study will improve our understanding of the basic mechanisms involved in the effects of IsoP's on retinal glutaminergic, GABAergic and dopaminergic transmission. Furthermore, these studies may reveal pharmacologically/toxicologically accessible sites for the action of IsoP's in the retina. We hope that observations made in this project will be applicable to diseases of the retina associated with the generation of free radicals and oxidative damage such as ischemia, glaucoma, diabetic retinopathy and age-related macular degeneration.

描述（由申请人提供）：异前列腺素（IsoP's）是一系列前列腺素样化合物，它们通过不依赖环加氧酶的非酶促、自由基催化的花生四烯酸过氧化而在体内大量形成。除了提供体内和体外氧化应激的可靠测量之外，IsoP 还可以在某些组织中发挥药理作用。文献综述表明，很少有研究探讨 IsoP 对中枢或外周组织神经递质释放的影响。尽管据报道 IsoP 可以调节前葡萄膜组织的交感神经传递，但没有研究调查这些化合物对视网膜神经传递的潜在调节作用。在本研究中，我们将测试 IsoP 可以在体外和体内调节视网膜中谷氨酸、γ-氨基丁酸 (GABA) 和多巴胺能传递的假设。本研究的总体目标是在体外和体内检查不同系列的 IsoP（A1、E1、E2、F1、F2 和 F3）对视网膜释放谷氨酸、GABA 和多巴胺的影响。因此，该项目的实验旨在回答以下问题：(i) 不同的 IsoP 是否会改变体外和体内谷氨酸、GABA 和多巴胺的释放和/或可用性？ (ii) IsoP 产生的效果与其他花生四烯酸代谢物（前列腺素和血栓素）的效果是否相当？ (iii) 突触前 IsoP 异质受体在这些化合物对体外和体内谷氨酸、GABA 和多巴胺的影响中起什么作用？我们预计本研究的结果将提高我们对 IsoP 对视网膜谷氨酰胺能、GABA 能和多巴胺能传递影响的基本机制的理解。此外，这些研究可能揭示 IsoP 在视网膜中的药理学/毒理学作用位点。我们希望该项目的观察结果能够适用于与自由基产生和氧化损伤相关的视网膜疾病，例如缺血、青光眼、糖尿病性视网膜病变和年龄相关性黄斑变性。