Analgesic efficacy of single and combined minor cannabinoids and terpenes

单一和组合次要大麻素和萜烯的镇痛功效

• 批准号: 10121270
• 负责人: Sara J Ward
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10121270
• 关键词: 3xTg-AD mouse; Achievement; Acids; Administrative Supplement; Adverse effects; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Analgesics; Animal Model; Anti-Inflammatory Agents; Beta-caryophyllene; Biological; Brain-Derived Neurotrophic Factor; Cannabinoids; Cannabis; Cannabis sativa plant; Cerebral Ischemia; Clinical; Cognitive; Combined Modality Therapy; Data; Dementia; Development; Dose; Ensure; Funding; Goals; Impaired cognition; Injury; Investigation; Learning; Legal; Length; Medical Marijuana; Memory; Minor; Molecular; Mus; Neuronal Plasticity; Neurons; Plants; Population; Property; Research; Rodent Model; Terpenes; Testing; Tetrahydrocannabinol; Therapeutic; base; behavior test; cannabigerol; executive function; experimental study; glial activation; interest; marijuana user; memory recognition; mouse model; neuroinflammation; neuroprotection; older patient; painful neuropathy; phytocannabinoid; pre-clinical; prevent; response; translational medicine

The primary goal of the funded R01 is to quantitatively test the hypothesis that combinations of four biologically active components of Cannabis sativa act synergistically to protect against the development of neuropathic pain. Experiments proposed in this supplement will test the hypothesis that these non-psychoactive compounds will ameliorate age- and Alzheimer’s related cognitive impairment through anti-inflammatory and neuroplastic mechanisms. While the primary psychoactive constituent of Cannabis ∆9-tetrahydrocannabinol (THC) is associated with cognitive adverse effects, the non-psychoactive phytocannabinoid cannabinoid (CBD) has shown improvements in learning and memory preclinically. Potential mechanisms of action of CBD for a range of therapeutic indications are currently under investigation, with its profound anti-inflammatory and neuroprotective properties of paramount interest. In addition to CBD, the minor cannabinoid cannabigerol (CBG), the acid form of THC THCA, and the terpene beta-caryophyllene (β-CP), are receiving increasing interest as potential anti-inflammatory agents. For example, we have recently demonstrated that β-CP prevents the development of neuropathic pain in rodent models and significantly decreases secondary injury in a mouse model of cerebral ischemia, with both effects correlating to decreased microglial activation. These data taken together compel further research to determine the effects of non-psychoactive Cannabis-based approaches for the treatment of age- and Alzheimer’s-related cognitive impairment/dementia. This is especially pressing given that older patients make up a large and growing population of Medical Cannabis users. Lastly, a key focus of the funded and proposed research is to determine interactive effects of these Cannabis constituents. So-called “entourage effects” of Cannabis constituents are anecdotally discussed at length, but empirical data are woefully lacking. Testing for such interactive effects requires rigorous dose response testing and analysis across single and combined agents. Animal modeling to test unique interactive effects of several Cannabis constituents provides a uniquely effective contribution to translational medicine, as executing such studies in a clinical setting is immensely more challenging and expensive. In the current supplement we propose to determine the efficacy of CBD, CBG, THCA, and β-CP alone and in combination on executive function and recognition memory in young and old mice, as well as 3xTg-AD mice. At the completion of behavioral testing, complementary immunohistochemical and molecular approaches will be utilized to examine the underlying neuroinflammatory mechanisms by characterizing the effects of single and combined agents on glial activation and neuronal and microglial BDNF expression. The assembled team has the expertise and collaborative relationship to ensure the achievement of the proposed project. The overall impact of the project will be to provide empirically derived evidence for key components of Cannabis representing non-psychoactive single and/or combined for the treatment of cognitive decline.

资助的R01的主要目标是定量检验以下假设。 大麻sativa行动的活跃成分协同抗体，以防止神经疗法的发展 疼痛。此补充中提出的实验将检验以下假设：这些非精神活性 化合物将通过抗炎和 神经塑性机制。而大麻的主要精神活性构成∆9四氢大麻酚 （THC）与认知不良反应有关，非精神活性大麻素大麻素（CBD） 已经显示出在学习和记忆方面的改进。 CBD的潜在作用机理 目前正在研究一系列治疗指示，其抗炎和 最高兴趣的神经保护特性。除CBD外，小大麻素大麻醇 （CBG），THC THCA的酸形式和萜烯β-蛋黄豆烯（β-CP）正在接受增加 兴趣作为潜在的抗炎药。例如，我们最近证明了β-CP 防止啮齿动物模型中神经性疼痛的发展，并显着减少次要损伤 大脑缺血的小鼠模型，两种作用都与小胶质细胞活化的降低相关。这些 数据一起迫使进一步的研究以确定非精神活性大麻的影响 治疗年龄和阿尔茨海默氏症相关的认知障碍/痴呆症的方法。尤其是 鉴于老年患者构成了大量医疗大麻使用者的大量且迫在眉睫。最后， 资助和拟议研究的重点是确定这些大麻的互动效果 成分。大麻构成的所谓“随行效应”是详细讨论的，但 缺乏经验数据。对这种交互作用的测试需要严格的剂量响应测试 以及对单个和组合代理的分析。动物建模以测试几种独特的交互作用 大麻构成为转化医学提供了独特的有效贡献 在临床环境中的研究更加挑战和昂贵。在当前的补充中 单独并组合执行CBD，CBG，THCA和β-CP的效率 年轻小鼠以及3XTG-AD小鼠的功能和识别记忆。完成 行为测试，完整的免疫组织化学和分子方法将用于检查 通过表征单一和联合药物对 神经胶质激活以及神经元和小胶质细胞BDNF表达。组装团队具有专业知识和 协作关系以确保拟议项目的实现。项目的总体影响 将提供代表非精神活性大麻的关键组成部分的经验得出的证据 单一和/或合并以治疗认知能力下降。