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.

项目概要 联合抗逆转录病毒疗法（cART）的成功极大地提高了人们的预期寿命 感染艾滋病毒。这导致了与年龄相关的显着神经认知功能的临床观察 感染艾滋病毒的人口老龄化带来的并发症。 HIV 相关炎症与 即使在接受 cART 治疗的个体中，过早衰老和与年龄相关的合并症的风险也会增加。现在， 艾滋病毒感染者出于娱乐或医疗目的使用大麻的比例高于一般人群 人口。然而，大麻素在艾滋病毒和衰老方面的作用在临床前仍未得到探索。由于使用 老年艾滋病毒感染者中使用医用大麻的比例持续上升，迫切需要调查 大麻素在艾滋病毒衰老过程中的后果。该提案的目标是弄清楚有利与否 大麻素对艾滋病毒和艾滋病毒引起的老年小鼠神经认知缺陷的有害影响。它一直 研究表明，大麻二酚 (CBD) 可以改善小鼠的空间记忆和识别记忆，并减少焦虑 阿尔茨海默病模型，表明其治疗与年龄相关的痴呆症的潜力。因此，我们 假设接触 CBD 会调节衰老小鼠的神经炎症和认知缺陷 艾滋病病毒。为了检验这一假设，C57BL/6J 雄性和雌性成年小鼠（16 个月大）将感染 小鼠嗜性 HIV，EcoHIV。 8 周后（18 个月大），一部分感染 EcoHIV 的小鼠将受到暴露 单独使用 CBD、单独使用抗逆转录病毒药物以及同时使用 CBD 和抗逆转录病毒药物 21 天。在具体目标 1 中，我们 认为 CBD 将调节与艾滋病毒和年龄相关的认知缺陷，特别是记忆和学习 功能，通过新物体识别测试和 Y 迷宫行为测试来测量。在具体目标 2 中，我们 假设 CBD 暴露会调节神经炎症、神经胶质表型和细胞衰老 在特定目标 1 中回收的感染了 EcoHIV 的老年小鼠的死后脑组织。 该提案中描述的内容将使我们能够确定可以介导的分子机制 感染艾滋病毒的老年大脑接触大麻素的后果。该项目的最终目标是 确定可以减少与年龄相关的神经退行性缺陷的潜在治疗靶点 与慢性艾滋病毒感染有关。