Effect of Isoprostanes on Retinal Transmitter Release

描述（由申请人提供）：异前列腺素（IsoP）是一系列在体内通过不依赖于环氧合酶的花生四烯酸的非酶促、自由基催化的过氧化而大量形成的类胡萝卜素化合物。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学作用。文献综述显示，很少有研究涉及IsoP对中枢或外周组织神经递质释放的影响。虽然IsoP已报道调节来自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中神经传递的潜在调节作用。在本研究中，我们将测试的假设，IsoP的可以调节谷氨酸，γ-氨基丁酸（GABA）和多巴胺能在视网膜中的传输在体外和体内。本研究的总体目标是检查不同系列的IsoP（A1、E1、E2、F1、F2和F3）在体外和体内对视网膜释放谷氨酸、GABA和多巴胺的影响。因此，本项目中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产生的作用与其他花生四烯酸代谢物（异花生四烯酸和血栓烷）的作用相似吗？(iii)突触前IsoP异源受体在这些化合物在体外和体内对谷氨酸、GABA和多巴胺的作用中起什么作用？我们预期，本研究的结果将提高我们对IsoP对视网膜多巴胺能、GABA能和多巴胺能传递的影响的基本机制的理解。此外，这些研究可以揭示IsoP在视网膜中作用的生物学/毒理学可及位点。我们希望在这个项目中所做的观察将适用于与自由基和氧化损伤的产生相关的视网膜疾病，如缺血，青光眼，糖尿病视网膜病变和年龄相关性黄斑变性。

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.