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症(ADC)是由 HIV-1病毒侵袭脑巨噬细胞、星形胶质细胞和小胶质细胞 触发涉及贡献小区类型的各种介体建立 一系列细胞因子介导的事件导致毒素的产生 造成神经元损伤。(HIV-1包膜蛋白，糖蛋白120 (Gp120)，将建立相同的神经毒性过程。)许多人 细胞因子介导的过程似乎涉及信号转导事件 它们具有抗氧化剂敏感的步骤，并导致各种 基因，包括转化生长因子-α和诱导型一氧化氮合酶。(Inos调解 产生大量的一氧化氮[NO]，或者它或它的一种 代谢物[如过氧亚硝酸盐]对大多数神经元是有毒的。)《校长》 调查员和他的同事们取得了新奇而引人注目的初步成果 可能有助于理解神经元损伤的数据，并提供导致 有可能治疗艾滋病痴呆症。他们已经发现，利用直接的NO 用gp120诱导新生大鼠模型的捕获技术 神经元发育延迟，高水平的NO被困在 一种神经保护化合物，PBN，不仅可以防止NO 但可防止gp120介导的神经元发育减慢。 脑细胞培养中gp120加多种细胞因子诱导iNOS基因表达 大量NO的表达和形成。这是通过以下方式防止的 PBN。这项拟议研究的长期目标是确定 NO在神经损伤中所起的作用，检查升级的作用 细胞因子介导的iNOS基因诱导和氧化事件，并确定 PBN及其相关化合物的神经保护作用机制 ADC的实验模型。此外，在ADC模型中得到的结果 将与艾滋病患者脑脊液分析得到的结果进行比较 认为所获得的知识将对 开发治疗ADC的潜在治疗方法。 具体目标是：(1)首先，确定NO和氧化的作用 损伤与特定细胞因子所起的中介作用 利用大鼠脑细胞培养和大鼠研究ADC相关的神经毒性 第二，确定诱导型一氧化氮合酶和基因的作用 PBN和PBN在神经毒性过程中特异性细胞因子的表达 几种相关化合物及其神经保护作用的研究 这些化合物；(2)建立gp120转基因小鼠模型。 星形胶质细胞中的表达可以在任何特定的时间被打开或关闭 动物的生活和进行研究，以确定iNOS和 特异性细胞因子基因表达在神经损伤中的作用；以及(3) 确定无氧化产物(NO2-、NO3-)以及是否被氧化 艾滋病患者脑脊液中蛋白质和特异性细胞因子的变化 参照他们的痴呆症程度和疾病分期 进步。

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.