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: 8072571
• 负责人: Valerie Toodle
• 金额: $ 2.12万
• 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/8072571
• 关键词: AIDS Dementia Complex; Acids; Anti-Retroviral Agents; Antifungal Agents; Astrocytes; Biological Assay; Blood - brain barrier anatomy; Brain; Carbon; Cell Death; Cell membrane; Cells; Cerebrospinal Fluid; Cessation of life; Clinical Trials; Cyclic AMP; Cytochrome P450; DNA; Diagnosis; Disease; Drug effect disorder; Environment; Enzymes; Ergosterol; FDA approved; Failure; Family; Fluconazole; Functional disorder; Grant; HIV; HIV Envelope Protein gp120; HIV Infections; HIV tat Protein; HIV-1; Healthcare; Impaired cognition; Impairment; In Vitro; Individual; Infection; Inflammatory; Injury; Laboratories; Lead; Mediating; Microglia; Mitochondria; Mitochondrial Proteins; Mycoses; Necrosis; Nerve Degeneration; Neurocognitive; Neuronal Injury; Neurons; Neuropathogenesis; Neuroprotective Agents; Neurotoxins; Nitrogen; Nitrous Oxide; Patients; Penetration; Pharmaceutical Preparations; Population; Production; Property; Proteins; Public Health; Reactive Oxygen Species; Research; Screening procedure; Sterol Biosynthesis Pathway; Toxin; Transgenic Mice; Triazoles; Tumor Necrosis Factor-alpha; Viral; Viral Proteins; Virus; Water; antiretroviral therapy; burden of illness; cell type; chemokine; drug development; drug structure; effective therapy; fight against; functional group; fungus; human TNF protein; in vivo; macrophage; member; monocyte; mouse model; neuroprotection; oxidative damage; phosphoric diester hydrolase; prevent; tumor

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.

艾滋病相关痴呆（HIV-associated dementia, hiv - ad）是当今医疗保健领域一个具有挑战性的疾病。这种疾病的发生是由于hiv感染的单核细胞和巨噬细胞通过血脑屏障进入大脑。这些被感染的细胞随后释放各种神经毒素，包括肿瘤坏死α (tnf - α)、氧化亚氮和在大脑中产生炎症环境的趋化因子。此外，HIV感染通常扩散到小胶质细胞，而星形胶质细胞潜伏感染。这两种细胞类型的感染可以导致HIV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导致未被HIV直接感染的神经元的严重损伤和死亡。神经元损伤和细胞死亡与hiv患者的认知功能障碍有直接关系；因此，神经保护剂将是对抗这种疾病的有力援助。我们实验室的初步研究已经确定了fda批准的抗真菌药物氟康唑作为抗HIV Tat蛋白和3-硝基本体酸的神经保护剂，3-硝基本体酸是一种毒素，用于模拟大脑中由HIV感染引起的氧化损伤、活性氧产生和随后的神经变性。申请人将通过确定药物对HIV gp120的活性、对神经祖细胞的作用以及药物的某些作用是否通过对线粒体或细胞膜的直接作用来介导，来描述用氟康唑观察到的神经保护作用。此外，这项拨款建议研究氟康唑对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负责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环磷酸腺苷（cAMP）水平降低，cAMP是一种重要的次级信使。我们计划研究这种对细胞内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的三唑官能团介导。