HIV ASSOCIATED NEUROTOXICITY AND NMDA ANTAGONISTS

HIV 相关神经毒性和 NMDA 拮抗剂

• 批准号: 6202088
• 负责人: STUART A LIPTON
• 金额: $ 24.77万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6202088
• 关键词: AIDS dementia complex; HIV envelope protein gp120; NMDA receptors; amantadine; animal breeding; biological signal transduction; cysteine endopeptidases; disease /disorder model; drug screening /evaluation; gene targeting; genetically modified animals; glia; infant animal; inhibitor /antagonist; injection /infusion; laboratory mouse; laboratory rat; macrophage; neuroprotectants; neurotoxins; nitric oxide; retinal ganglion

The neurological manifestations of AIDS affect approximately half of the children infected with HIV-1 and perhaps on-quarter to one-third of adults. Many children with AIDS display delayed milestones and even frank cognitive and motor decline, causing substantial development disabilities and mental retardation. Quite apart from super-infections with opportunistic organisms and malignancy, at least some degree 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, gp120. Neurons are injured in this process and may undergo apoptosis, and at least part of their damage is accounted for by the macrophage and possibly astrocyte toxic factors leading to over-excitation of glutamate receptors, especially of the N-methyl-D-aspartate. (NMDA) subtype. Therefore, in Project, our group of investigators studies the effects of clinically-tolerated NMDA antagonists in preventing the neuronal injury engendered by gp120 in the following model systems: (a) in vitro in rodent cerebrocortical cultures, (b) in vivo in a rodent retinal model using intravitreal injection of gp120, (c) in vivo in a gp120- transgenic mouse model, and (d) in vivo in a SCID (subacute combined immunodeficiency) mouse model of AIDS dementia produced by intracerebral injection of HIV-infected human monocytes. Here we propose to use the clinically-tolerated NMDA antagonists developed in Projects. We will also study apoptotic signaling pathways that may be present in AIDS brains, including those mediated by nitric oxide and caspases (similar to pathways triggered by NMDA and hypoxia-ischemia in Project). To accomplish these goals, transgenic and knockout mice that disrupt these signaling pathways will be used for the intravitreal injection of gp120 or will be crossed with gp120-transgenic mice. The resulting gp120-injected or bigenic mice will be analyzed histologically by confocal laser scanning microscopy and by magnetic resonance spectroscopy (MRS) in the Program's CORE facilities to determine if disruption of these signalling pathways ameliorates gp120-induced damage. It is anticipated that these preclinical studies investigating the role of the NMDA receptor and it signaling pathways to neuronal cell injury may lead to new treatment of the neurological manifestations of AIDS. In the previous grant period, this has already been realized to some extent with one of the NMDA receptor antagonist developed by this Program Project (memantine) going into a nation-wide clinical trial for AIDS dementia.

艾滋病的神经系统表现影响大约一半的感染了HIV-1的儿童，也许会影响到三分之一的成年人。许多患有艾滋病的儿童表现出延迟的里程碑，甚至坦率的认知和运动衰落，导致了大量发展障碍和智力障碍。除了与机会主义生物和恶性肿瘤的超级感染外，艾滋病中CNS的某种程度似乎与脑巨噬细胞感染HIV-1后释放的毒素或受到其外套蛋白GP120刺激后，似乎与脑巨噬细胞释放的毒素最紧密相关。在此过程中，神经元受伤并可能患有凋亡，至少部分损伤是由巨噬细胞和可能的星形胶质细胞毒性因素造成的，导致谷氨酸受体过度激发，尤其是N-甲基-D-天冬氨酸。 （NMDA）亚型。因此，在项目中，我们的研究人员研究了临床耐受性的NMDA拮抗剂在以下模型系统中GP120引起的神经元损伤的影响：（a）在啮齿动物脑皮层培养物中的体外，（a）在体内使用啮齿动物脑皮层介绍的啮齿动物模型（b）在体内使用啮齿动物的模型，使用了gp120的rodent recterial Modele travitial Model nove gp120（c），gp120（c），gp120（c），gp120（c）in gp120（c）。 （d）在脑内注射HIV感染的人类单核细胞中产生的AIDS痴呆症的SCID（亚急性组合免疫缺陷）的体内。在这里，我们建议使用项目中开发的临床耐受性NMDA拮抗剂。我们还将研究艾滋病大脑中可能存在的凋亡信号传导途径，包括一氧化氮和胱天蛋白酶（类似于NMDA触发的途径和Project Projectia-dypoxia-Ischemia）。为了实现这些目标，破坏这些信号通路的转基因和敲除小鼠将用于玻璃体内注射GP120，或将与GP120-转基因小鼠交叉。将通过共聚焦激光扫描显微镜以及该程序的核心设施中的磁共振光谱（MRS）在组织学上分析所得的GP120注射或临床小鼠，以确定这些信号通路的破坏是否会增强GP120诱导的损坏。可以预料，这些研究NMDA受体作用及其神经元细胞损伤的信号传导途径的临床前研究可能会导致对艾滋病神经系统表现的新治疗。在上一个赠款期间，该计划项目（美容）开发的NMDA受体拮抗剂之一在一定程度上已经实现了这一目标，该计划正在进行艾滋病痴呆症的全国性临床试验。