HIV ASSOCIATED NEUROTOXICITY AND NMDA ANTAGONISTS

HIV 相关神经毒性和 NMDA 拮抗剂

• 批准号: 6108663
• 负责人: EVAN B DREYER
• 金额: $ 30.79万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6108663
• 关键词: AIDS dementia complex; HIV envelope protein gp120; NMDA receptors; amantadine; electron spin resonance spectroscopy; embryo /fetus; gene deletion mutation; genetically modified animals; glia; human fetus tissue; infant animal; inhibitor /antagonist; laboratory mouse; laboratory rat; macrophage; magnetic resonance imaging; neurons; neurotoxins; nitric oxide; nitric oxide synthase

The neurological manifestations of AIDS affect approximately half of the children infected with HIV-1 and perhaps one-third of the adults. Many children with AIDS display delayed milestones and even frank cognitive and motor decline, causing substantial developmental disabilities and mental retardation. Quite apart from superinfections with opportunistic organisms and malignancy, damage in the CNS in AIDS appears to be most closely associated with toxins released by brain macrophages after they have been infected by HIV-1 or stimulated by its coat protein, gpl20. Neurons are injured in this process, and at least part of their damage is accounted for by the macrophage toxic factors leading to overexcitation of glutamate receptors, especially of the N-methyl-D- aspartate (NMDA) subtype. Therefore, in Project III our group of investigators studies the effects of clinically-tolerated NMDA antagonists in preventing the neuronal injury engendered by gp120 (or a fragment of gpl20). In published experiments, our laboratory has shown that NMDA antagonists can effectively prevent gpl20-induced neuronal injury in vitro in mixed neuronal/glial cultures. Subsequently, this work has been corroborated by several other laboratories. In the proposed studies, we will draw on the results of Projects I and II to use the clinically-tolerated NMDA antagonists developed in those studies. We will use these NMDA antagonists to prevent gpl20-mediated neurotoxicity, first in vitro and then in vivo, using both recombinant and purified gpl20 injections into rat pups as well as a transgenic- gp120 mouse model. The Specific Aims of Project III are as follows: 1. To test the clinically-tolerated NMDA antagonists memantine (and related adamantanes) and redox-related forms of nitric oxide in vitro and in vivo for their ability to ameliorate HIV-l coat protein (gpl20) toxicity in-- (a) rat and human primary central neuronal/glial cultures incubated with gpl20, and in (b) rat pups in vivo injected with picomole quantities of gpl20, which in preliminary studies produce striking lesions in the cortex, and in (c) mice in vivo containing a gpl20 transgene that has been demonstrated to be associated with neuronal damage. 2. To test the potential contribution of neuronal nitric oxide to the CNS damage in the gpl20-transgenic mice. To do this we will analyze by histology, by magnetic resonance imaging and spectroscopy (MRI/MRS), and by electron parmagnetic resonance (EPR) spectroscopy the offspring of GFAP-gpl20 transgenic mice crossed with neuronal nitric oxide synthase (NOS) knockout mice. It is anticipated that these preclinical studies investigating the role of the NMDA receptor and its downstream activation of NOS may lead to new treatments of the neurological manifestations of AIDS.

艾滋病的神经表现影响大约一半 感染了HIV-1的儿童，也许是成年人的三分之一。许多 有艾滋病的孩子展示延迟的里程碑，甚至弗兰克认知 和汽车下降，导致大量发育障碍和 智力低下。除了机会主义的超级感染外 生物和恶性肿瘤，艾滋病中枢神经系统的损害似乎是最大的 与脑巨噬细胞释放的毒素紧密相关 已被HIV-1感染或受到其外套蛋白GPL20的刺激。 在此过程中，神经元受伤，至少部分受伤 由巨噬细胞的毒性因素所解释 谷氨酸受体过度兴奋，特别是N-甲基-D- 天冬氨酸（NMDA）亚型。因此，在第三项目中我们的小组 研究人员研究临床耐受性NMDA的影响 防止GP120造成的神经元损伤的拮抗剂（或 GPL20的片段）。在已发表的实验中，我们的实验室表明 NMDA拮抗剂可以有效防止GPL20诱导的神经元 混合神经元/神经胶质培养物中的体外损伤。随后，这个 其他几个实验室也证实了工作。在 拟议的研究，我们将借鉴I和II项目的结果 使用临床上耐受性的NMDA拮抗剂 研究。我们将使用这些NMDA拮抗剂来防止GPL20介导 神经毒性，首先在体外，然后在体内，使用两个重组 并纯化的GPL20注射大鼠幼崽以及转基因 - GP120鼠标模型。项目III的具体目的如下： 1。测试临床耐受性的NMDA拮抗剂美容（和 相关的金刚烷）和一氧化氮与氧化还原相关的形式体外 并体内能够改善HIV-L外套蛋白（GPL20）的能力（GPL20） 毒性 （A）大鼠和人类原发性中央神经/神经胶质培养物 与GPL20一起孵育 （b）体内注射脚趾虫量的大鼠幼崽 GPL20在初步研究中产生引人注目的病变 在皮层和 （c）体内含有GPL20转基因的小鼠 证明与神经元有关 损害。 2。测试神经元一氧化氮对 GPL20-转基因小鼠的中枢神经系统损伤。为此，我们将通过 组织学，通过磁共振成像和光谱法（MRI/MRS），以及 通过电子par磁共振（EPR）光谱法的后代 与神经元一氧化氮合酶交叉的GFAP-GPL20转基因小鼠 （NOS）淘汰小鼠。 预计这些临床前研究研究了角色 NMDA受体及其下游活化的NOS可能导致 艾滋病神经系统表现的新疗法。