Neurocognitive implications of cannabidiol (CBD) while aging with HIV

项目总结 联合抗逆转录病毒疗法(CART)的成功大大延长了人们的预期寿命 艾滋病毒携带者。这导致了与年龄相关的神经认知的临床观察。 艾滋病毒老龄化人口中的并发症。与艾滋病毒相关的炎症被认为与 即使在接受购物车治疗的个体中，过早衰老和增加与年龄相关的合并症的风险也是如此。目前， 艾滋病毒携带者出于娱乐或医疗目的吸食大麻的比率高于一般人。 人口。然而，在艾滋病毒和老龄化的背景下，大麻类药物仍未得到临床前的研究。就像使用 在老年艾滋病毒感染者中医用大麻的数量继续上升，迫切需要调查 艾滋病毒老化过程中大麻素的后果。这项提案的目标是揭示有益的与 大麻素对艾滋病毒和艾滋病毒诱导的老年小鼠神经认知障碍的有害影响。一直以来 研究表明，大麻二醇(CBD)可改善小鼠的空间记忆和再认记忆，并降低焦虑 阿尔茨海默病的模型，表明它对老年性痴呆的治疗潜力。因此，我们 假设暴露于CBD将调节衰老小鼠的神经炎症和认知缺陷 爱滋病毒。为了验证这一假设，C57BL/6J雄性和雌性成年小鼠(16个月大)将感染 嗜鼠艾滋病病毒，生态艾滋病病毒。8周后(18个月大)，感染EcoHIV的小鼠的一部分将被暴露 单用CBD，单用抗逆转录病毒药物，同时加用CBD和抗逆转录病毒药物，疗程21天。在具体目标1中，我们 假设CBD将调节HIV和年龄相关的认知缺陷，特别是记忆和学习 功能，通过新型物体识别测试和Y迷宫行为测试进行测量。在具体目标2中，我们 假设CBD暴露将调节神经炎症、神经胶质表型和细胞衰老 EcoHIV感染和老龄小鼠死后脑组织有针对性地恢复1.实验 这项提案中所描述的将使我们能够确定可能调节 感染艾滋病毒的老年人大脑暴露于大麻类药物的后果。这个项目的最终目标是 寻找一个潜在的治疗靶点，以减少与年龄相关的神经退行性变缺陷 与慢性艾滋病毒感染有关。

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.