Synergistic neurotoxicity of speedball and HIV toxins

速度球和 HIV 毒素的协同神经毒性

• 批准号: 7684414
• 负责人: Richard J. Noel
• 金额: $ 14.81万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684414
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Address; Affect; Antioxidants; Area; Astrocytes; Basal Ganglia; Biological; Brain; Brain region; Cessation of life; Cocaine; Coculture Techniques; Cognition Disorders; Cognitive; Complex; Data; Defect; Dementia; Dependence; Development; Disease; Drug Combinations; Drug abuse; Environment; Epidemic; Future; Giant Cells; Goals; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Hippocampus (Brain); Human; Impairment; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Intervention; Lead; Learning; Life Expectancy; Memory; Microglia; Minor; Modeling; Morbidity - disease rate; Morphine; Motor; Nature; Nerve Degeneration; Nervous System Trauma; Neurocognitive; Neurons; Neuropathogenesis; Neurotoxins; Opioid; Oxidants; Oxidative Stress; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Physiological; Prevalence; Proteins; Rattus; Research; Research Personnel; Risk; Role; Severities; Substantia nigra structure; Syndrome; Testing; Toxic effect; Toxin; Viral; Viral Load result; Viral Proteins; Virus Diseases; Virus Replication; Work; base; brain cell; combinatorial; data modeling; design; drug of abuse; improved; in vivo; instrument; loss of function; macrophage; model development; mortality; motor disorder; motor learning; multidrug abuse; neuropathology; neurotoxicity; novel; prevent; public health relevance; substance abuser; theories; tool; translational study; treatment strategy; virotoxins

DESCRIPTION (provided by applicant): This proposal addresses a critical aspect of the HIV-1 epidemic by seeking to better understand the roles of viral proteins and polydrug abuse on the development of HIV neurocognitive disorders (HAND). HIV quickly enters the brain and infects macrophages and microglia rather than neurons. While HAART can effectively control this replication, HAND prevalence is not reduced in parallel, indicating that virus replication is not responsible for all neuropathology. Viral proteins that may come from infected astroctyes even during viral suppression are thought to cause neuronal damage both directly and indirectly. Individual drugs of abuse, such as cocaine or morphine, synergize with viral toxins through effects on astrocytes to exacerbate inflammation and oxidative stress. However, polydrug use predominates among substance abusers in the US and no studies to date have examined the combinations of drugs with HIV neurotoxins. The first aim of this proposal is targeted to better understand the potential synergy between polydrug abuse (speedball) and HIV neurotoxins. A second aim is to develop a rat model of speedball to study the motor and memory effects of polydrug abuse with these virotoxins. These goals will be approached using application of speedball and Tat or Vpr to in vitro primary cultures of astrocytes and neurons to study exacerbated oxidative stress and inflammation as a possible mechanism for synergistic neurotoxicity. In addition, rats treated with cocaine, morphine or speedball will be assessed for motor and memory function followed by post mortem histological analyses of prooxidant environment and neuronal damage and death. This research will lead to a better understanding of the overlapping roles of viral toxins and multiple drug abuse in generating oxidative stress and inflammation that appear to be a key to understanding the development and progression of HAND. In addition, the work will generate an essential new tool to study, in a biological setting, the extent and nature of the motor and memory defects that occur in HIV neurocognitive disorders, including the mechanistic role of oxidants. This model is expected to be instrumental in the design of translational studies for discovery of new treatment strategies to prevent HAND development and progression in a drug abuse setting. PUBLIC HEALTH RELEVANCE: HIV-1 infection and drug abuse are two medically and socially important issues in the US. These epidemics exist independently, but also have significant overlap including a possible synergistic contribution to neurocognitive disorders. This proposal seeks to better define and understand the combined effects of drug abuse and HIV infection in neuropathology, as well as to generate baseline data on to permit targeted in vivo studies of the contributions of HIV and drugs to NeuroAIDS. Such information can be used to improve long term management and reduce the morbidity associated with these illnesses.

描述（由申请人提供）：该提案通过寻求更好地了解病毒蛋白和多种药物滥用对 HIV 神经认知障碍 (HAND) 发展的作用，解决了 HIV-1 流行病的一个关键方面。 HIV 迅速进入大脑并感染巨噬细胞和小胶质细胞，而不是神经元。虽然HAART可以有效控制这种复制，但HAND患病率并没有同时降低，这表明病毒复制并不是所有神经病理学的原因。即使在病毒抑制期间，也可能来自受感染星形细胞的病毒蛋白被认为会直接和间接引起神经元损伤。个别滥用药物，如可卡因或吗啡，通过影响星形胶质细胞与病毒毒素产生协同作用，加剧炎症和氧化应激。然而，在美国，多种药物滥用在药物滥用者中占主导地位，迄今为止还没有研究检查药物与艾滋病毒神经毒素的组合。该提案的第一个目的是更好地了解多种药物滥用（速球）和艾滋病毒神经毒素之间的潜在协同作用。第二个目标是开发快速球大鼠模型，以研究这些病毒毒素滥用多种药物对运动和记忆的影响。这些目标将通过应用 Speedball 和 Tat 或 Vpr 进行星形胶质细胞和神经元的体外原代培养来实现，以研究加剧的氧化应激和炎症作为协同神经毒性的可能机制。此外，将评估用可卡因、吗啡或速球治疗的大鼠的运动和记忆功能，然后对促氧化环境以及神经元损伤和死亡进行死后组织学分析。这项研究将有助于更好地了解病毒毒素和多种药物滥用在产生氧化应激和炎症方面的重叠作用，这似乎是了解 HAND 发生和进展的关键。此外，这项工作还将产生一种重要的新工具，用于在生物学环境中研究艾滋病毒神经认知障碍中发生的运动和记忆缺陷的程度和性质，包括氧化剂的机制作用。该模型预计将有助于设计转化研究，以发现新的治疗策略，以防止药物滥用环境中 HAND 的发展和进展。公共卫生相关性：HIV-1 感染和药物滥用是美国的两个医学和社会重要问题。这些流行病独立存在，但也有显着的重叠，包括可能对神经认知障碍产生协同作用。该提案旨在更好地定义和理解药物滥用和艾滋病毒感染对神经病理学的综合影响，并生成基线数据，以便对艾滋病毒和药物对神经艾滋病的贡献进行有针对性的体内研究。此类信息可用于改善长期管理并降低与这些疾病相关的发病率。