HYDROGEN PEROXIDE AND RETINAL NEUROTRANSMITTER RELEASE

说明(申请人的说明)：活性氧代谢物，氢 过氧化氢存在于玻璃体、神经视网膜和色素中。 某些哺乳动物的上皮组织。尽管氧化应激一直是 与一些视网膜疾病有关，如老年性黄斑变性 和糖尿病视网膜病变，还没有研究涉及潜在的药理作用 H_2O_2对小鼠脑内神经递质释放的毒性作用 组织。这些研究是必要的，因为我们有证据表明，过氧化氢可以改变 大鼠前葡萄膜交感神经释放去甲肾上腺素 几种哺乳动物物种。此外，据报道，过氧化氢可以改变 在大脑中释放多巴胺和谷氨酸。在本研究中，我们将 验证过氧化氢诱导的氧化应激可以修改输出的假设 哺乳动物视网膜神经元中的多巴胺和谷氨酸。总体目标 本研究的目的是探讨H_2O_2对细胞释放的影响。 体外和体内视网膜中的多巴胺和谷氨酸。实验 因此，在本项目中，已被设计为回答以下问题 问题：(I)过氧化氢是否改变多巴胺的释放和/或可获得性 几种哺乳动物视网膜中的谷氨酸？它的作用是什么 突触前自身受体在过氧化氢引起的影响中？(Ii)排名第二 钙、环核苷酸和花生四烯酸代谢物等信使 H202对多巴胺能和谷氨酸能的影响 变速箱？(Iii)空气中的过氧化氢浓度会否增加 玻璃体体液改变内源性多巴胺和谷氨酸水平 视网膜？(4)抑制过氧化氢酶活性是否会增加 内源性过氧化氢在眼睛中的浓度，这反过来会改变 视网膜中的多巴胺和谷氨酸水平？(V)生化变化 玻璃体内注射H_2O_2诱导的细胞形态改变 这种氧化剂会引起视网膜组织的改变吗？我们预计结果会是 这项研究将提高我们对基本机制的理解 H_2O_2对视网膜多巴胺能和谷氨酸能的影响 变速箱。此外，我们希望这一项目的结果将是 适用于与氧化应激有关的视网膜疾病，如 缺血、糖尿病视网膜病变和老年性黄斑变性。

DESCRIPTION (Applicant's Description): The reactive oxygen metabolite, hydrogen peroxide (H2O2) is present in the vitreous humor, neural retina and pigment epithelium of some mammalian species. Although oxidative stress has been implicated in some retinal disorders such as age-related macular degeneration and diabetic retinopathy, no study has addressed the potential pharmacological or toxicological effect of H2O2 on the release of neurotransmitters in this tissue. These studies are needed because we have evidence that H2O2 can alter the release of norepinephrine from sympathetic nerves in the anterior uvea of several mammalian species. Furthermore, H2O2 has been reported to alter the release of dopamine and glutamate in the brain. In the present study, we will test the hypothesis that oxidative stress induced by H2O2 can modify the output of dopamine and glutamate from mammalian retinal neurons. The overall objective of the present study is to investigate the effect of H2O2 on the release of dopamine and glutamate from the retina both in vitro and in vivo. Experiments in the present project have, therefore, been designed to answer the following questions: (i) does H2O2 alter the release and/or availability of dopamine and glutamate from mammalian retina of several species? What is the role of presynaptic autoreceptors in the effects caused by H2O2? (ii) are second messengers such as calcium, cyclic nucleotides and arachidonic acid metabolites involved in the effects caused by H202 on dopaminergic and glutaminergic transmission? (iii) will an increase in the concentration of H2O2 in the vitreous humor alter the endogenous levels of dopamine and glutamate in the retina? (iv) will the inhibition of catalase activity increase the concentration of endogenous H2O2 in the eye, which in turn will alter the levels of dopamine and glutamate in the retina? (v) does biochemical change induced by intravitreally-administered H2O2 correlate with morphological alterations of retinal tissues by this oxidant? We anticipate that the results of the present study will improve our understanding of the basic mechanisms involved in the effects of H2O2 on retinal dopaminergic and glutaminergic transmission. Furthermore, we hope that the findings of this project will be applicable to diseases of the retina associated with oxidative stress such as ischemia, diabetic retinopathy and age-related macular degeneration.