The Elucidation of the Neuroprotective Effects of Triazoles Against HIV

艾滋病相关性痴呆（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。这些受感染的细胞然后释放各种神经毒素，包括肿瘤坏死因子α（TNF-α），一氧化二氮和趋化因子，在大脑中产生炎症环境。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除了先前提到的神经毒素之外的HIV蛋白质达特和gp 120的释放。病毒蛋白和神经毒素的释放导致神经元的严重损伤和死亡，而这些神经元并没有直接被HIV感染。神经元损伤和细胞死亡与诊断为HIVAD的患者中观察到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援助。我们实验室的初步研究已经确定FDA批准的抗真菌剂氟康唑作为抗HIV达特蛋白和3-硝基丙酸的神经保护剂，3-硝基丙酸是一种用于模拟氧化损伤、活性氧产生和随后由脑中HIV感染引起的神经变性的毒素。申请方将通过确定药物对HIV gp 120的活性、对神经祖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作用介导，来表征药物氟康唑观察到的神经保护作用。此外，该资助计划研究氟康唑对HIV蛋白转基因小鼠模型的体内影响。最后，该基金建议研究氟康唑对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），一个重要的第二信使的水平下降。我们计划研究这种对细胞内cAMP的抑制是否是氟康唑的神经保护作用的原因，以及这些作用是否是由药物结构中存在的三唑官能团介导的。

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.