The Elucidation of the Neuroprotective Effects of Triazoles Against HIV

三唑类药物对 HIV 的神经保护作用的阐明

• 批准号: 7929330
• 负责人: Valerie Toodle
• 金额: $ 3.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2012-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929330
• 关键词: AIDS Dementia Complex; Acids; Antifungal Agents; Astrocytes; Blood - brain barrier anatomy; Brain; Cell Death; Cell membrane; Cells; Cessation of life; Cyclic AMP; Diagnosis; Disease; Drug effect disorder; Environment; FDA approved; Fluconazole; Functional disorder; Grant; HIV; HIV Envelope Protein gp120; HIV Infections; HIV tat Protein; Healthcare; Impaired cognition; Individual; Infection; Inflammatory; Injury; Laboratories; Lead; Mediating; Microglia; Mitochondria; Necrosis; Neurocognitive; Neuronal Injury; Neurons; Neuroprotective Agents; Neurotoxins; Nitrous Oxide; Patients; Pharmaceutical Preparations; Population; Production; Proteins; Public Health; Reactive Oxygen Species; Research; Toxin; Transgenic Mice; Triazoles; Tumor Necrosis Factor-alpha; Viral Proteins; antiretroviral therapy; burden of illness; cell type; chemokine; drug structure; fight against; functional group; human TNF protein; in vivo; macrophage; monocyte; mouse model; oxidative damage; public health relevance; tumor

DESCRIPTION (provided by applicant): HIV-associated dementia (HIVAD) is a challenging illness in healthcare field today. This disease occurs as a result of HIV-infected monocytes and macrophages crossing into the brain via the blood-brain barrier. These infected cells then release various neurotoxins including tumor necrosis alpha (TNF-alpha), nitrous oxide, and chemokines which creates an inflammatory environment in the brain. Additionally, HIV infection typically spreads to microglia while astrocytes become latently infected. The infection of these two cell types can lead to the release of the HIV proteins Tat and gp120 in addition to the neurotoxins previously mentioned. The release of the viral proteins and neurotoxins leads to significant injury and death in neurons, which are not directly infected by the HIV. Neuronal injury and cell death are directly related to the cognitive dysfunctions observed in patients diagnosed with HIVAD; therefore, a neuroprotective agent would be a powerful aid in the fight against this illness. Preliminary studies in our laboratory have identified the FDA-approved antifungal agent fluconazole as a neuroprotective agent against HIV Tat protein and 3-nitroproprionic acid, a toxin used to mimic the oxidative damage, reactive oxygen species production, and ensuing neurodegenration resulting form HIV infection in the brain. The applicant will characterize the neuroprotective effects observed with the drug fluconazole by determining the activity of the drug against HIV gp120, its effect on neuroprogenitor cells, and whether some actions of the drug are mediated by a direct effect on the mitochondria or the cell membrane. Additionally, this grant proposes to investigate the in vivo effects of fluconazole on HIV protein transgenic mouse models. Finally, this grant proposes to investigate the mechanism by which fluconazole is responsible for its neuroprotective effects. Our preliminary studies show that the presence of fluconazole leads to decreased intracellular levels of cyclic adenosine monophosphate (cAMP), an important secondary messenger. We plan to investigate if this inhibition of intracellular cAMP is responsible for fluconazole's neuroprotective effects, and if these effects are mediated by the triazole functional groups present in the drug's structure. PUBLIC HEALTH RELEVANCE: The research is important to public health since HIV-associated neurocognitive disorder (HAND) is becoming more and more prevalent in HIV-infected populations. Additionally, although the use of antiretroviral therapy is now becoming more accessible worldwide, antiretroviral therapy is unable to halt the progression of neurocognitive dysfunction observed in individuals with HAND. Therefore, the identification of fluconazole as a potent neuroprotective agent would greatly reduce the disease burden of HAND.

描述(申请人提供)：HIV相关性痴呆(HIVAD)是当今医疗保健领域的一种具有挑战性的疾病。这种疾病的发生是艾滋病毒感染的单核细胞和巨噬细胞通过血脑屏障进入大脑的结果。这些被感染的细胞然后释放各种神经毒素，包括肿瘤坏死因子、一氧化二氮和趋化因子，从而在大脑中创造炎症环境。此外，HIV感染通常会扩散到小胶质细胞，而星形胶质细胞则会潜伏感染。这两种细胞类型的感染可导致艾滋病毒蛋白Tat和gp120的释放，以及前面提到的神经毒素。病毒蛋白和神经毒素的释放会导致神经元的严重损伤和死亡，而这些神经元并不直接感染艾滋病毒。神经元损伤和细胞死亡与被诊断为HIVAD的患者的认知功能障碍直接相关；因此，神经保护剂将是对抗这种疾病的有力辅助。我们实验室的初步研究证实，FDA批准的抗真菌剂氟康唑是一种神经保护剂，可对抗HIV Tat蛋白和3-硝基本酸，3-硝基本酸是一种毒素，用于模拟HIV感染引起的大脑中的氧化损伤、活性氧的产生和随后的神经退化。申请者将通过确定药物对艾滋病毒gp120的活性、对神经前体细胞的影响以及药物的某些作用是否通过对线粒体或细胞膜的直接影响来表征药物观察到的神经保护作用。此外，这项资助还建议研究氟康唑对HIV蛋白转基因小鼠模型的体内影响。最后，这项拨款建议调查氟康唑对其神经保护作用的机制。我们的初步研究表明，氟康唑的存在导致细胞内重要的第二信使环磷酸腺苷(CAMP)水平下降。我们计划调查这种对细胞内cAMP的抑制是否与氟康唑的神经保护作用有关，以及这些作用是否由药物结构中存在的三唑官能团介导。 公共卫生相关性：这项研究对公共卫生很重要，因为艾滋病毒相关的神经认知障碍(HAND)在艾滋病毒感染人群中越来越普遍。此外，尽管抗逆转录病毒疗法的使用现在在世界范围内变得更加容易，但抗逆转录病毒疗法无法阻止手部患者神经认知功能障碍的进展。因此，将氟康唑确定为一种有效的神经保护剂将大大减轻手部的疾病负担。