AIDS DEMENTIA AND THE PROTECTIVE EFFECT OF PBN

描述（改编自摘要）：许多研究支持这一概念 与艾滋病感染相关的痴呆综合症（ADC）是由以下原因引起的： HIV-1病毒侵入脑巨噬细胞、星形胶质细胞和小胶质细胞 触发涉及贡献细胞类型的各种介质， 一系列的尼古丁介导的事件导致毒素的产生， 导致神经元损伤。 (The HIV-1包膜蛋白，糖蛋白120 （gp 120），将建立相同的神经毒性过程。许多 甜菜碱介导的过程似乎涉及信号转导事件 其具有抗氧化剂敏感的步骤，并引起各种 基因，包括TGF-α和诱导型（iNOS）。 (iNOS介导 生产大量的一氧化氮[NO]和它或它的一个 代谢物[例如，过氧亚硝酸盐]对大多数神经元有毒。校长 调查员和他的同事已经获得了新颖和惊人的初步 这些数据可能有助于理解神经元损伤， 可能治疗艾滋病痴呆症 他们发现，利用直接的NO 在新生大鼠模型中的捕获技术，其中GP 120给药引起 延迟的神经元发育，高水平的NO被困在 一种神经保护化合物PBN不仅可以阻止NO的产生， 但防止了神经元发育中GP 120介导的减慢。 在脑细胞培养中，gp 120与多种细胞因子联合诱导iNOS基因表达， 表达和形成大量的NO。这是防止 PBN。 拟议研究的长期目标是确定 一氧化氮在神经损伤中的作用，检查 苦参碱介导的iNOS基因诱导和氧化事件，并确定 PBN及相关化合物的神经保护作用机制 ADC的实验模型 此外，在ADC模型中获得的结果 将与从艾滋病患者CSF分析中获得的结果进行比较 认为所获得的知识将是有价值的， 开发治疗ADC的潜在治疗方法。 具体目的是：（1）首先，确定NO和氧化应激的作用， 损伤和特定细胞因子的介导作用， ADC相关神经毒性，利用大鼠脑细胞培养和大鼠 第二，确定iNOS和基因的作用 在使用PBN的神经毒性过程中表达特异性细胞因子， 几种相关化合物，并确定神经保护作用的 这些化合物;（2）开发小鼠转基因模型，其中gp 120 星形胶质细胞中的表达可以在任何特定的时间“开启”或“关闭”， 动物的生活和进行研究，以确定的作用，iNOS和 特异性细胞因子基因表达在神经损伤中起作用;和（3） 确定是否有NO氧化产物（NO2-，NO3-），以及氧化 蛋白质和特定的细胞因子，在艾滋病患者的CSF中发生改变， 参考他们的痴呆程度和疾病分期 进展

DESCRIPTION (adapted from the Abstract): Much research supports the notion that the dementia complex associated with AIDS infection (ADC), is caused by the HIV-1 virus invading the brain macrophages, astrocytes, and microglia triggering various mediators involving contributing cell types setting up a series of cytokine-mediate events leading to the production of toxins which cause neuronal damage. (The HIV-1 envelope protein, glycoprotein 120 (gp120), will set up the same neurotoxic processes.) Many of the cytokine-mediated processes appear to involve signal transduction events which have antioxidant-sensitive steps and cause the induction of various genes, including TGF-alpha and inducible (iNOS). (iNOS mediates the production of large levels of nitric oxide [NO] and either it or one of its metabolites [e.g., peroxynitrite] is toxic to most neurons.) The Principal Investigator and his coworkers have obtained novel and striking preliminary data that may be useful in understanding neuronal damage and offer leads to possibly treat AIDS dementia. They have found, utilizing a direct NO trapping technique in a rat neonate model where gp120 administration causes delayed neuronal development, that high levels of NO are trapped in the brain and that a neuroprotective compound, PBN, not only prevents the NO build-up but prevents the gp120-mediated slowdown in neuronal development. In brain cell culture, gp120 plus various cytokines induce iNOS gene expression and the formation of large amounts of NO. This is prevented by PBN. The long-range goal of the proposed research is to define the role that NO plays in neurological damage, examine the role of escalating cytokine-mediated iNOS gene induction and of oxidative events, and ascertain the neuroprotective mechanism of action of PBN and related compounds in experimental models of ADC. In addition, the results obtained in ADC models will be compared to those obtained from the analysis of CSF of AIDS patients with the view that the knowledge obtained will be valuable in the development of potential therapeutic approaches to the treatment of ADC. The specific aims are: (1) first, to ascertain the role of NO and oxidative damage and the mediating effect that specific cytokines play in neurotoxicity associate with ADC, utilizing rat brain cell culture and rat neonate models and, second, to ascertain the role of iNOS and the gene expression of specific cytokines in neurotoxic processes using PBN and several related compounds and to ascertain the neuroprotective action of these compounds; (2) to develop a mouse transgenic model wherein gp120 expression in astrocytes can be turned "on" or "off" at any specific time in the animal's life and conduct studies to ascertain the role that iNOS and specific cytokine gene expression plays in neurologic damage; and (3) to ascertain whether NO oxidation products (NO2-, NO3-), as well as oxidized protein and specific cytokines, are altered in the CSF of AIDS patients in reference to their degree of dementia and their staging in terms of disease progression.