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.

被资助的R01的主要目标是定量测试四种生物学组合的假设 大麻有效成分协同抗神经病变作用 疼痛。本附录中提出的实验将检验这样的假设，即这些非精神活性 化合物将通过抗炎和改善与年龄和阿尔茨海默氏症相关的认知障碍 神经再生机制。而大麻的主要精神活性成分∆9-四氢大麻酚 (THC)与认知不良反应有关，即非精神活性植物大麻素(CBD) 已经显示出临床前学习和记忆方面的改善。CBD的潜在作用机制 目前正在研究一系列治疗适应症，其深刻的抗炎和 至高无上利益的神经保护特性。除了CBD，次要的大麻类大麻酚 四氢呋喃的酸性形式(CbG)和萜烯-β-石竹烯(β-CP)的含量正在增加 兴趣是潜在的抗炎药。例如，我们最近证明了β-CP 在啮齿动物模型中防止神经病理性疼痛的发展，并显著减少继发性损伤 脑缺血的小鼠模型，这两种作用都与小胶质细胞激活减少有关。这些 综合起来的数据迫使进一步的研究来确定非精神活性大麻的影响 治疗与年龄和阿尔茨海默氏症相关的认知障碍/痴呆的方法。这是特别的 考虑到老年患者构成了大量且不断增长的医用大麻使用者，这一点迫在眉睫。最后， 已资助和拟议的研究的一个关键重点是确定这些大麻的相互影响 选民。关于大麻成分的所谓“随行效应”，坊间有很长的讨论，但是 令人遗憾的是，经验数据非常缺乏。这种交互效应的测试需要严格的剂量响应测试 以及跨单一和联合代理的分析。动物建模，以测试几个 大麻成分为转化医学提供了独特有效的贡献，因为执行这样的 临床环境下的研究更具挑战性，成本也更高。在本期的补编中，我们 建议确定CBD、CBG、THCA和β-CP单独或联合应用对执行力的影响 年轻和老年小鼠以及3xTg-AD小鼠的功能和再认记忆。在完成时 将利用行为测试、互补的免疫组织化学和分子方法来检查 通过表征单一和联合用药对神经炎症的影响来研究潜在的神经炎性机制 神经胶质细胞活化及神经元和小胶质细胞BDNF表达。集结的团队拥有专业知识和 建立协作关系，以确保拟议项目的实现。该项目的整体影响 将为大麻代表非精神活性的关键成分提供经验性证据 单用和/或联合治疗认知功能减退。