Anti-inflammatory Effects of Novel Minor Cannabinoids and Terpenes on Cellular and Murine Models of HIV and HIV Proteins

新型次要大麻素和萜烯对 HIV 和 HIV 蛋白的细胞和小鼠模型的抗炎作用

基本信息

批准号：
10663954
负责人：
Nicole M Ashpole
金额：
$ 34.48万
依托单位：
UNIVERSITY OF MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663954
关键词：
Acetic Acids Analgesics Anti-Inflammatory Agents Anti-Retroviral Agents Antiinflammatory Effect Astrocytosis Beta-caryophyllene Biological Assay Brain Brain region CNR1 gene CNR2 gene Cannabidiol Cannabinoids Cannabis Capsid Proteins Cell Culture Techniques Cell model Cells Central Nervous System Chemicals Clinical Complement Consumption Data Dorsal Dose Edema Enteric Nervous System Etiology Experimental Designs Exposure to Female Frequencies Freund&apos s Adjuvant GPR55 receptor GTP-Binding Proteins Genetic Transcription Gliosis Glycoproteins HIV HIV-1 Human In Vitro Individual Infection Inflammation Inflammatory Injections Intestines Intractable Pain Laboratory Research Lamivudine Libraries Marijuana Mechanics Mediating Microglia Midbrain structure Minor Modality Morphology Mus Nerve Fibers Neurons Opioid Outcome Pain Parietal Lobe Patient Self-Report Patients Peripheral Peripheral Blood Mononuclear Cell Persons Pharmacodynamics Placebos Plasma Population Prevalence Production Property Proteins Refractory Reporting Research Rodent Model Role Spinal Cord Spinal Ganglia Symptoms Terpenes Testing Tetrahydrocannabinol Thalamic structure Therapeutic Therapeutic Effect Tissues Trans-Activators Transcription Coactivator Transgenic Mice Viral Viremia Visceral Visceral pain Volatile Oils Work abacavir antagonist antinociception antiretroviral therapy astrogliosis cannabichromene chronic constriction injury chronic pain cytokine cytotoxicity efficacious treatment ileum improved in vivo inflammatory pain insight male marijuana use monocyte mouse model novel novel therapeutics opioid use painful neuropathy response sensory neuropathy

项目摘要

Summary Approximately 50% of HIV-infected patients suffer from intractable pain and many individuals self-report the consumption of cannabis for alleviating their symptoms. However, data are still limited on the effects of cannabis in the HIV-infected, cART-treated population. The compound most studied is Δ9-THC, which exerts psychoactive and addictive effects that limit therapeutic potential. Yet, there are over 120 minor cannabinoids and 200 terpenes in cannabis and our renowned Marijuana Research Laboratory has found many of them hold non-psychoactive, therapeutic effects. We identified cannabis constituents that reduce HIV-mediated inflammation/astrogliosis in cell culture and HIV-protein mediated visceral pain in mice. We hypothesize that several minor cannabinoids and terpenes will complement cART to ameliorate viremia, inflammation, and cytotoxicity caused by infectious HIV- 1. Moreover, we anticipate several of these compounds to ameliorate the inflammatory, mechanical, visceral, and neuropathic pain states promoted by cART or HIV-1 proteins. Aim 1 will determine the important cannabis constituents and targets that modulate HIV-mediated viremia and inflammation in vitro. Utilizing our extensive library of cannabinoids, terpenes, and volatile oils, we will screen a high-cannabidiol (CBD) mixture and 44 pure minor cannabinoids and terpenes against human peripheral blood mononuclear cells or microglia that are mock- infected or infected with HIV-1IIIB or HIV-1BaL. Viremia, cytokine production, and cytotoxicity will be assessed and the pharmacodynamic mechanisms will be subsequently examined using antagonists to CB1, CB2, and GPR55. Aim 2 will determine the in vivo anti-nociceptive and analgesic effects of minor cannabinoids and terpenes in rodent models of HIV-1 protein/cART-related inflammatory, thermal, visceral, and neuropathic pain. Dose- dependent anti-inflammatory, anti-hyperalgesic, and anti-nociceptive effects of cannabichromene, 10β-hydroxy- 8-tetrahydrocannabinol, and β–caryophyllene will be the pure compounds of focus, along with High-CBD extract (and other anti-inflammatory leads identified in Aim 1). These constituents will be assessed in male and female transgenic mice that express (or do not express) the HIV-1 Tat or gp120 proteins. Mice will be maintained on cART to assess potential improvements or interactions with cannabinoid-related outcomes. Aim 3 will determine the important central and enteric nervous system inflammatory mechanisms that are influenced by cannabinoids and terpenes following HIV-1 protein/cART exposure. Pain-related brain regions, spinal cord, dorsal root ganglion, ileum, edema, and plasma collected in Aim 2 will be assessed for cytokine production. Brain and ileum will be assessed for CB1 or CB2 G-protein activity via [35S]GTPγS assay as well as neuron morphology and monocyte-derived cell and astrogliosis. TThese studies will provide insight into the mechanisms by which minor cannabinoids and terpenes act, will reveal the anti-viremic, anti-inflammatory, and antinociceptive potential of non-psychoactive cannabis constituents, and will elucidate therapeutics for HIV-related and non-HIV-related, intractable pain states.

概括大约50％的艾滋病毒感染患者患有棘手的疼痛，许多人自我报告消费大麻以减轻症状。但是，数据仍然受到大麻影响的限制在受HIV感染的，手推车处理的人群中。最多研究的化合物是δ9-THC，它导出精神活性以及限制治疗潜力的成瘾作用。然而，有超过120个次要大麻素和200台萜烯在大麻和我们著名的大麻研究实验室中，其中许多人具有非精神活性，治疗作用。我们确定了大麻构成的大麻构成，以减少HIV介导的感染/星形胶质细胞增多细胞培养和HIV蛋白介导的小鼠内脏疼痛。我们假设几种小大麻素和萜烯将补充推车以改善因感染性HIV-引起的病毒血症，感染和细胞毒性。 1。此外，我们预计其中几种化合物可以改善炎症，机械，内脏，由CART或HIV-1蛋白促进的神经性疼痛态。 AIM 1将决定重要的大麻构成和靶标可在体外调节HIV介导的病毒血症和炎症。利用我们的广泛大麻素，萜烯和挥发性油的库，我们将筛选一个高大麻二酚（CBD）混合物和44个纯净的混合物针对人类外周血单核细胞或小胶质细胞的次要大麻素和萜烯，是模拟的感染或感染HIV-1IIIB或HIV-1BAL。将评估病毒血症，细胞因子产生和细胞毒性，并随后将使用拮抗剂对CB1，CB2和GPR55对药效机制进行检查。 AIM 2将确定次要大麻素和萜烯在体内抗伤害感受和镇痛作用 HIV-1蛋白/卡车相关炎症，热，内脏和神经性疼痛的啮齿动物模型。剂量- 依赖性的抗炎，抗高温和抗吸引力的大麻，10β-羟基 - 8-四氢大麻醇和β-蛋黄烯将成为纯化的焦点化合物，高CBD提取物（以及AIM 1中确定的其他抗炎铅）。这些构成将在男性和女性中进行评估表达（或不表达）HIV-1 TAT或GP120蛋白的转基因小鼠。老鼠将维持卡车评估潜在的改进或与大麻素相关结果的相互作用。 AIM 3将确定受大麻素影响的重要中心神经系统炎症机制 HIV-1蛋白/推车暴露后的萜烯。与疼痛有关的大脑区域，脊髓，背根将评估AIM 2中收集的Ganglion，回肠，水肿和等离子体的细胞因子产生。大脑和回肠将通过[35S]GTPγS分析以及神经元的形态和神经元的形态和CB2 G蛋白活性评估CB1或CB2 G蛋白活性单核细胞衍生的细胞和星形胶质症。 These研究将洞悉次要的机制大麻素和萜烯法案将揭示抗病毒，抗炎和抗热性的潜力非精神活性大麻构成，并将阐明与HIV相关和非HIV相关的治疗棘手的疼痛状态。