EXCITATORY AMINO ACIDS IN GLAUCOMA

青光眼中的兴奋性氨基酸

• 批准号: 2163707
• 负责人: EVAN B. DREYER
• 金额: $ 16.04万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2163707
• 关键词: NMDA receptors; amantadine; calcium indicator; digital imaging; disease /disorder model; drug tolerance; glaucoma; glutamates; glutathione; human subject; inhibitor /antagonist; laboratory rat; neuropharmacology; neuroprotectants; neurotoxins; nitric oxide; nitroglycerin; oxidation reduction reaction; receptor expression; retinal ganglion; tissue /cell culture; toxicology; voltage /patch clamp

Glaucoma is a disease marked in the majority of cases by a significant elevation of intraocular pressure. This intolerable level of pressure compromises the optic nerve, and leads to the loss of retinal ganglion cells. Accordingly, the majority of therapeutic interventions are specifically directed at pressure control. This grant suggests a second etiology for the neuronal loss seen in glaucoma The Principal Investigator has demonstrated an elevated level of the excitatory amino acid glutamate in the vitreous of patients with glaucoma. This agent, known to be toxic to retinal ganglion cells, may therefore contribute to the cell death seen in glaucoma. It is suggested that neuronal injury engendered by this excitatory amino acid is mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. This form of toxicity has been well documented in a wide variety of central nervous system (CNS) diseases; given that retinal ganglion cells are indeed part of the CNS, it is not surprising that glutamate is toxic to these neurons as well. If glutamate indeed plays a role in glaucomatous visual loss, this suggests several new therapies for the management of the patient with glaucoma. This grant proposes to explore several clinically safe inhibitors of NMDA toxicity. Initial studies will be performed in vitro; however the demonstrated clinical utility of the proposed drugs for other conditions should expedite their use in a clinical scenario in the future. This grant proposes the following: (l) In Preliminary Studies, elevated vitreous levels of glutamate are reported in a limited number of patients with glaucoma. This data base will be expanded to confirm these preliminary results. More samples will also establish if stratification by glaucoma diagnosis or other factors identifies a subpopulation of glaucoma patients with higher levels of glutamate that will derive particular benefit from treatment with the proposed agents. (2) To develop a rodent model of chronic glutamate/NMDA retinal toxicity, as well as testing in vivo the compounds characterized in vitro under (3) & (4). (3) To test adamantane derivatives, such as memantine (which we have shown is an NMDA open-channel blocker), for their ability to prevent acute NMDA receptor-mediated neurotoxicity in retinal ganglion cells incubated with glutamate or NMDA. (4) To characterize and test reagents, including nitric oxide (NO)- producing drugs and glutathione, that down regulate NMDA receptor activity by oxidation of a redox modulatory site, in order to prevent chronic NMDA receptor-mediated neurotoxicity.

青光眼是一种疾病，在大多数情况下都有明显的 眼压升高。这种无法忍受的压力 损害视神经，导致视网膜神经节的丧失 细胞。因此，大多数治疗干预措施是 专门针对压力控制。这笔赠款意味着第二次 青光眼中神经元丢失的病因学 已经证明兴奋性氨基酸谷氨酸水平升高 在青光眼患者的玻璃体中。这种已知有毒的毒剂 视网膜神经节细胞，因此可能导致细胞死亡 青光眼。有人认为，由此引起的神经元损伤 兴奋性氨基酸由N-甲基-D-天冬氨酸(NMDA)介导 谷氨酸受体的亚型。这种形式的毒性一直很好 记录了多种中枢神经系统(CNS)疾病； 鉴于视网膜神经节细胞确实是中枢神经系统的一部分，它不是 令人惊讶的是，谷氨酸对这些神经元也是有毒的。 如果谷氨酸确实在青光眼视力丧失中起作用，这 建议了几种新的治疗方法来管理患者 青光眼。这项拨款建议探索几种临床安全的 NMDA毒性的抑制剂。初步研究将在体外进行； 然而，建议的药物对其他疾病的临床效用证明 在未来的临床场景中，条件应该会加快它们的使用。 这笔赠款提出了以下建议： (L)在初步研究中，玻璃体中谷氨酸水平升高是 在有限数量的青光眼患者中有报道。这个数据库 将扩大以确认这些初步结果。将会有更多的样品 也要确定是否通过青光眼诊断或其他因素进行分层 确定青光眼患者中有较高水平的 谷氨酸，将从治疗中获得特别的好处 推荐的代理。 (2)建立谷氨酸/NMDA视网膜慢性毒性动物模型。 以及在体内测试在体外表征的化合物(3) &(4)。 (3)测试金刚烷衍生物，如美金刚(我们已经展示了 是一种NMDA开放通道阻滞剂)，因为它们能够预防急性NMDA 受体介导的视网膜神经节细胞神经毒性 谷氨酸或NMDA。 (4)鉴定和测试试剂，包括一氧化氮(NO)- 生产药物和谷胱甘肽，下调NMDA受体活性 通过氧化氧化还原调节位点，以防止慢性NMDA 受体介导的神经毒性。