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 HIV 感染者患有顽固性疼痛，许多人自我报告吸食大麻以缓解症状然而，有关大麻效果的数据仍然有限。在 HIV 感染者、接受 cART 治疗的人群中，研究最多的化合物是 Δ9-THC，它具有精神活性。然而，有超过 120 种次要大麻素和 200 种萜烯。大麻和我们著名的大麻研究实验室发现其中许多具有非精神活性，我们发现大麻成分可以减少艾滋病毒介导的炎症/星形胶质细胞增生。我们研究了几种次要的大麻素和细胞培养物和 HIV 蛋白介导的内脏疼痛。萜烯将补充 cART 以改善由传染性 HIV 引起的病毒血症、炎症和细胞毒性 1. 此外，我们预计其中一些化合物可以改善炎症、机械、内脏、 cART 或 HIV-1 蛋白促进的神经性疼痛状态将决定重要的大麻。利用我们广泛的体外调节艾滋病毒介导的病毒血症和炎症的成分和靶标。大麻素、萜烯和挥发油库，我们将筛选高大麻二酚 (CBD) 混合物和 44 种纯针对模拟的人外周血单核细胞或小胶质细胞的次要大麻素和萜烯将评估感染或感染 HIV-1IIIB 或 HIV-1BaL 的病毒血症、细胞因子的产生和细胞毒性。随后将使用 CB1、CB2 和 GPR55 的拮抗剂检查药效机制。目标 2 将确定次要大麻素和萜烯在体内的抗伤害和镇痛作用 HIV-1 蛋白/cART 相关炎症、热痛、内脏痛和神经性疼痛的啮齿动物模型。依赖大麻环烯、10β-羟基-的抗炎、抗痛觉过敏和抗伤害作用 8-四氢大麻酚和 β-石竹烯以及高 CBD 提取物将成为焦点的纯化合物（以及目标 1 中确定的其他抗炎先导成分）将在男性和女性中进行评估。表达（或不表达）HIV-1 Tat 或 gp120 蛋白的转基因小鼠将被维持。 cART 评估潜在的改善或与大麻素相关结果的相互作用将确定。受大麻素影响的重要中枢和肠神经系统炎症机制和 HIV-1 蛋白/cART 暴露后的萜类化合物。将评估目标 2 中收集的神经节、回肠、水肿和血浆的细胞因子产生。将通过 [35S]GTPγS 测定以及神经元形态来评估 CB1 或 CB2 G 蛋白活性这些研究将深入了解未成年人的机制。大麻素和萜烯的作用，将揭示其抗病毒血症、抗炎和抗菌潜力非精神活性大麻成分，并将阐明艾滋病毒相关和非艾滋病毒相关的治疗方法，顽固性疼痛状态。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HIV-1 Tat Upregulates the Receptor for Advanced Glycation End Products and Superoxide Dismutase-2 in the Heart of Transgenic Mice.

HIV-1 Tat 上调转基因小鼠心脏中高级糖基化终产物和超氧化物歧化酶 2 的受体。

DOI：
发表时间：
2022-10-04
期刊：
影响因子：
0
作者：
Qrareya, Alaa N;Wise, Nason S;Hodges, Emmanuel R;Mahdi, Fakhri;Stewart Jr, James A;Paris, Jason J
通讯作者：
Paris, Jason J

Physiological Corticosterone Attenuates gp120-Mediated Microglial Activation and Is Associated with Reduced Anxiety-Like Behavior in gp120-Expressing Mice.

生理皮质酮减弱 gp120 介导的小胶质细胞激活，并与 gp120 表达小鼠的焦虑样行为减少相关。