Selegiline, Oxidative Stress and MRS in HIV Dementia

司来吉兰、氧化应激和 MRS 在 HIV 痴呆中的作用

• 批准号: 6659906
• 负责人: GIOVANNI SCHIFITTO
• 金额: $ 54.95万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659906
• 关键词: AIDS /HIV neuropathy; AIDS dementia complex; HIV infections; antioxidants; bioimaging /biomedical imaging; biomarker; brain metabolism; cerebrospinal fluid; clinical research; cognition disorders; deprenyl; human immunodeficiency virus; human subject; human tissue; magnetic resonance imaging; major histocompatibility complex; neuropsychological tests; nuclear magnetic resonance spectroscopy; oxidative stress; pathologic process; virus RNA

DESCRIPTION: (provided by applicant) Cognitive impainnent is a common complication of HIV- I infection that can lead to dementia. Markers of immune activation in the central nervous system (CNS) have been shown to best correlate with the degree of cognitive impairment. Interestingly, most products of immune activation induce cytotoxicity via induction of oxidative stress. In this regard, our preliminary data indicate that levels of oxidative stress, measured by cerebrospinal fluid (CSF) induced changes in neuronal mitochondrial membrane potential and CSF levels of protein carbonyl, correlate with the severity of HIV-associated cognitive impairment. The mitochondrial membrane potential abnormalities can be reversed by drugs with antioxidant properties including selegiline (L-deprenyl). It is noteworthy that two preliminary studies suggest that selegiline may improve cognitive impairment associated with HIV infection. Based on these observations, the AIDS Clinical Trials Group (ACTG) has approved a large multicenter trial with selegiline (A5090). We hypothesize that oxidative stress is an important mechanism in the pathogenesis of HIV-associated cognitive impairment and will correlate with markers of cerebral injury as measured by magnetic resonance spectroscopy (MRS) and with established predictors of HIV-associated cognitive impairment including CSF HIV RNA (viral load) and B2 microglobulin levels. We also hypothesize that antioxidant compounds such as selegiline will improve the cognitive performance and metabolic markers of cerebral injury in HIV infected individuals and that this response will correlate with the levels of oxidative stress. We propose to further investigate the role of oxidative stress in HIV-associated cognitive impairment by addressing the following specific aims: 1) to compare markers of oxidative stress in the CSF among HIV infected subjects with and without cognitive impairment and 11W negative controls; 2) to assess the relationship between levels of oxidative stress and CSF HIV viral load and B2-microglobulin levels; 3) to assess the relationship between levels of oxidative stress and in vivo brain metabolism, as measured by MRS in HIV infected subjects with and without cognitive impairment; 4) to assess the effect of selegiline on CSF markers of oxidative stress and on in vivo brain metabolism (MRS) in subjects with 11W-associated cognitive impairment and to correlate changes in markers of oxidative stress with MRS and cognitive performance. The proposed study will take advantage of the ACTG supporting A5090 study and of the existing MRS consortium infrastructure that will allow us to perform multicenter MRS studies.

描述：（由申请人提供）认知障碍是常见的 艾滋病病毒感染并发症，可导致痴呆症。免疫标志物 中枢神经系统（CNS）的激活已被证明是最好的 与认知障碍的程度相关。有趣的是，大多数产品 免疫激活的诱导细胞毒性通过诱导氧化应激。在 在这方面，我们的初步数据表明氧化应激水平， 通过脑脊液（CSF）诱导的神经元线粒体的变化来测量 膜电位和CSF中蛋白质羰基的水平，与 HIV相关认知障碍的严重程度。线粒体膜 具有抗氧化特性的药物可以逆转潜在的异常 包括司来吉兰（L-丙炔苯丙胺）。值得注意的是，两个初步 研究表明，司来吉兰可以改善认知障碍相关的， 艾滋病病毒感染。根据这些观察，艾滋病临床试验组 （ACTG）已经批准了一项关于司来吉兰（A5090）的大型多中心试验。我们 假设氧化应激是发病机制中重要机制 与艾滋病相关的认知障碍，并将与 通过磁共振波谱（MRS）测量的脑损伤， 已确定的HIV相关认知损害（包括CSF HIV）的预测因子 RNA（病毒载量）和B2微球蛋白水平。我们还假设， 抗氧化化合物如司来吉兰将改善认知能力 以及HIV感染者脑损伤的代谢标志物， 这种反应将与氧化应激水平相关。我们建议 进一步研究氧化应激在HIV相关认知功能中的作用， 通过解决以下具体目标来实现：1）比较 有和没有HIV感染者CSF中的氧化应激 认知障碍和11 W阴性对照; 2）评估 氧化应激水平与CSF HIV病毒载量和B2-微球蛋白之间的关系 水平; 3）评估氧化应激水平与 体内脑代谢，如通过MRS在HIV感染受试者中测量的， 无认知障碍; 4）评估司来吉兰对CSF的影响 氧化应激标志物和受试者体内脑代谢（MRS） 与11 W相关的认知障碍，并与 氧化应激与MRS和认知能力的关系。拟定的研究将 利用ACTG支持A5090研究和现有MRS 联盟基础设施，使我们能够进行多中心MRS 问题研究