EXCITATORY AMINO ACIDS IN GLAUCOMA

青光眼是一种在大多数病例中以显著的 眼内压升高这种无法忍受的压力 损害视神经，导致视网膜神经节缺失 细胞因此，大多数治疗干预措施是 特别针对压力控制。这一发现表明， 青光眼中神经元丢失的病因 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。这种已知有毒的药剂 视网膜神经节细胞，因此可能有助于细胞死亡， 在青光眼中。提示此作用可引起神经元损伤， 兴奋性氨基酸由N-甲基-D-天冬氨酸（NMDA）介导 谷氨酸受体亚型。这种形式的毒性一直很好 在多种中枢神经系统（CNS）疾病中有记录; 鉴于视网膜神经节细胞确实是中枢神经系统的一部分， 令人惊讶的是，谷氨酸对这些神经元也是有毒的。 如果谷氨酸确实在昏迷性视力丧失中起作用， 提出了几种新的治疗方法， 青光眼这项拨款旨在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，所提出的药物对其他疾病的临床效用已得到证实， 条件应加快其在未来的临床情况下使用。 该赠款提出以下建议： (l)在初步研究中，玻璃体中谷氨酸水平升高， 在有限数量的青光眼患者中报告。该数据库 将扩大以证实这些初步结果。更多样品将 还确定是否根据青光眼诊断或其他因素进行分层 确定了一个青光眼患者亚群， 谷氨酸盐，这将从用谷氨酸盐治疗中获得特别的益处。 建议代理人 (2)为了开发慢性谷氨酸/NMDA视网膜毒性的啮齿动物模型， 以及在体内测试根据（3）在体外表征的化合物， （4）. (3)为了测试金刚烷衍生物，如美金刚（我们已经证明 是一种NMDA开放通道阻滞剂），因为它们能够预防急性NMDA 视网膜神经节细胞中受体介导的神经毒性 谷氨酸或NMDA。 (4)表征和测试试剂，包括一氧化氮（NO）- 产生药物和谷胱甘肽，下调NMDA受体活性 通过氧化还原调节位点的氧化，以防止慢性NMDA 受体介导的神经毒性

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.