Neurocognitive implications of cannabidiol (CBD) while aging with HIV

大麻二酚 (CBD) 在艾滋病毒衰老过程中对神经认知的影响

• 批准号: 10641920
• 负责人: Myosotys Rodriguez
• 金额: $ 14.75万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641920
• 关键词: Acceleration; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animals; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anxiety; Astrocytes; Autopsy; Behavior assessment; Brain; CNR1 gene; Cannabidiol; Cannabinoids; Cannabis; Cell Aging; Characteristics; Chronic; Clinical; Cognition; Cognitive deficits; Consumption; Cyclin-Dependent Kinase Inhibitor; Dementia; Development; Disease; Drug Kinetics; Effectiveness; Elderly; Exposure to; Female; Flow Cytometry; Fractals; General Population; Genes; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-associated neurocognitive disorder; Histologic; Immune; Immunohistochemistry; In Vitro; Individual; Inflammaging; Inflammation; Intervention; JAK2 gene; Learning; Life Expectancy; Liquid Chromatography; Longevity; Measures; Mediating; Medical; Medical Marijuana; Memory; Methodology; Molecular; Morphology; Mus; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurologic Deficit; Opioid; Organ; Pain management; Parkinson Disease; Pathway interactions; Patients; Persons; Phenotype; Play; Population; Premature aging syndrome; Process; Property; Recreation; Regimen; Reporting; Rest; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; STAT1 gene; Serum; TP53 gene; Testing; Therapeutic; Viral; Viral Load result; Western Blotting; age related; aged; aging brain; aging population; antiretroviral therapy; behavior test; brain tissue; chronic pain management; cognitive change; comorbidity; emtricitabine; experience; experimental study; human old age (65+); immune activation; immunosenescence; improved; in vivo; male; marijuana use; marijuana user; memory recognition; mitochondrial membrane; mouse model; neuroAIDS; neuroinflammation; neuroprotection; non-drug; normal aging; novel; object recognition; older patient; pre-clinical; premature; prevent; prospective; senescence; success; tandem mass spectrometry; therapeutic target

PROJECT SUMMARY The success of combined antiretroviral therapy (cART) has drastically improved the life expectancy of people living with HIV. This has resulted in the clinical observations of significant age-related neurocognitive complications among the population aging with HIV. HIV-associated inflammation has been implicated in premature aging and increased risk of age-associated comorbidities even in cART-treated individuals. Currently, people living with HIV are using cannabis, for recreational or medical purposes, at higher rates than the general population. However, cannabinoids in the context of HIV and aging remain preclinically unexplored. As the use of medical cannabis among older HIV individuals continues to rise, there is an urgent need to investigate the consequences of cannabinoids during aging with HIV. The goal of this proposal is to unravel the beneficial versus the detrimental effects of cannabinoids on HIV and HIV-induced neurocognitive deficits in aged mice. It has been shown that cannabidiol (CBD) improves both spatial and recognition memory and decreases anxiety in a mouse model of Alzheimer’s disease, suggesting its therapeutic potential for age‐related dementia. Therefore, we hypothesize that exposure to CBD will modulate neuroinflammation and cognitive deficits in mice that aged with HIV. To test this hypothesis, C57BL/6J male and female adult mice (at 16-months old) will be infected with the mouse-tropic HIV, EcoHIV. After 8 weeks (at 18-months old), a subset of EcoHIV-infected mice will be exposed to CBD alone, antiretrovirals alone, and concomitant CBD and antiretrovirals for 21 days. In Specific Aim 1, we posit that CBD will modulate HIV- and age-associated cognitive deficits, specifically memory, and learning functions, measured by the novel object recognition test and the Y-maze behavioral test. In Specific Aim 2, we posit that CBD exposure will modulate neuroinflammation, glial phenotypes, and cellular senescence in postmortem brain tissue of EcoHIV-infected and aged mice recovered in Specific Aim 1. The experiments described in this proposal will allow us to determine the molecular mechanisms that could mediate the consequences of cannabinoids exposure in the HIV-infected aged brain. The ultimate goal of this project is to identify a potential therapeutic target that could reduce age-related neurodegenerative deficits associated with chronic HIV infection.

项目摘要 联合抗逆转录病毒疗法（CART）的成功大大改善了人们的预期寿命 与艾滋病毒一起生活。这导致了与年龄相关的显着神经认知的临床观察 艾滋病毒衰老的人口并发症。艾滋病毒相关的炎症已暗示 即使在手推车处理的个体中，与年龄相关的合并症的风险过早和增加的风险也会增加。现在， 患有艾滋病毒的人正在使用大麻，用于娱乐或医疗目的，比一般的速度更高 人口。然而，在艾滋病毒和衰老的背景下，大麻素仍然是出乎意料的。作为使用 老年艾滋病毒个体中医用大麻的大麻不断上升，迫切需要调查 艾滋病毒衰老期间大麻素的后果。该提议的目的是揭开有益与 大麻素对艾滋病毒和艾滋病毒诱导的老年小鼠神经认知缺陷的有害作用。它一直 表明大麻二酚（CBD）可以改善空间和识别记忆，并减少鼠标的动画 阿尔茨海默氏病的模型，表明其与年龄相关的痴呆症的治疗潜力。因此，我们 假设暴露于CBD会调节神经炎症，并在年龄的小鼠中定义认知 艾滋病病毒。为了检验该假设，C57BL/6J男性和雌性小鼠（在16个月大）将被感染 小鼠 - 循环艾滋病毒，生态学。 8周后（在18个月大）之后，将暴露一部分Ecohiv感染的小鼠 单独使用CBD，单独使用抗逆转录病毒，以及伴随的CBD和抗逆转录病毒病。在特定目标1中，我们 认为CBD会调节HIV和年龄相关的认知定义，特别是记忆和学习 通过新颖的对象识别测试和Y迷宫行为测试来衡量的功能。在特定的目标2中，我们 认为CBD暴露会调节神经炎症，神经胶质表型和细胞感应 在特定目标1中回收的生态感染和老化小鼠的验尸脑组织。实验 该提案中描述的将使我们能够确定可以介导的分子机制 大麻素暴露于HIV感染的老年大脑中的后果。这个项目的最终目标是 确定可以减少与年龄有关的神经退行性缺陷的潜在治疗靶标 与慢性HIV感染有关。