HYDROGEN PEROXIDE AND RETINAL NEUROTRANSMITTER RELEASE

描述（申请人描述）：活性氧代谢物，氢 过氧化物（H2 O2）存在于玻璃体液、神经视网膜和色素中 某些哺乳动物的上皮。虽然氧化应激一直是 与一些视网膜疾病如年龄相关性黄斑变性有关 和糖尿病视网膜病变，没有研究已经解决了潜在的药理学 或毒理学效应的H2 O2对释放的神经递质，在这一点上， 组织.这些研究是必要的，因为我们有证据表明H2 O2可以改变 前葡萄膜交感神经释放去甲肾上腺素 几种哺乳动物此外，据报道H2 O2可以改变 释放多巴胺和谷氨酸在本研究中，我们将 测试H2 O2诱导的氧化应激可以改变输出的假设 多巴胺和谷氨酸的合成。总体目标 本研究的目的是研究H_2O_2对释放的影响， 多巴胺和谷氨酸从视网膜在体外和体内。实验 因此，在本项目中， 问题：（i）H2 O2是否会改变多巴胺的释放和/或可用性， 几种哺乳动物视网膜中的谷氨酸的作用是什么 突触前自身感受器在H2 O2？(ii)是第二 信使如钙、环核苷酸和花生四烯酸代谢物 参与H2 O2对多巴胺能和多巴胺能神经元的作用 传输？(iii)将在H2 O2浓度的增加， 玻璃体液改变多巴胺和谷氨酸的内源性水平， 视网膜？(iv)过氧化氢酶活性的抑制是否会增加 眼内内源性H2 O2的浓度，这反过来又会改变 视网膜中多巴胺和谷氨酸的水平(v)生物化学变化 诱导的玻璃体内给药H2 O2与形态学相关 这种氧化剂会改变视网膜组织吗我们预计， 本研究的结论将有助于我们更好地理解 参与H2 O2对视网膜多巴胺能和多巴胺能的影响 传输此外，我们希望该项目的结果将 适用于与氧化应激相关的视网膜疾病， 局部缺血、糖尿病视网膜病变和年龄相关性黄斑变性。

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.