Cannabinoid Acids as Antiinflammatory Agents

描述（由申请人提供）：本提案的总体目标是确定生物化学和分子机制，其中大麻素酸不具有精神活性，调节参与类风湿性关节炎患者关节组织损伤的启动和传播的细胞（巨噬细胞、滑膜细胞）的功能。待研究的大麻素酸包括阿佳酸（AjA）和四氢大麻酚-11酸。这些化合物不改变行为，口服，不损伤胃粘膜。AjA是四氢大麻酚（THC）羧酸代谢物THC-11-oic acid的合成非精神活性类似物，口服给药可预防关节炎动物模型中的关节软骨和骨损伤。初步研究表明，在体外向细胞中加入大麻素酸抑制几种炎性细胞因子的基因表达，并增强细胞凋亡。口服AjA可减弱活化单核细胞产生IL-11 β。该提议的主要假设是大麻素酸拮抗转录因子NF κ B的活化，这是由于和/或不依赖于过氧化物酶体增殖物激活受体γ（PPARy）的活化，导致细胞凋亡的增强和NF κ B靶基因（IL-1、IL-6、IL-8、考克斯-2）的下调。还将研究类花生酸在大麻素酸作用中的作用。细胞将从健康志愿者、骨关节炎和类风湿性关节炎患者中获得。大麻素酸将在体外添加到细胞中。将离体研究AjA口服给药前后从健康志愿者获得的细胞。设计实验以确定大麻素酸是否是PPARy的真正配体，并研究大麻素酸改变NFkB信号传导的机制。调查将包括使用基因转染，蛋白质印迹和免疫显微镜。该提案的完成将使人们更好地了解大麻素酸的抗氧化和免疫调节作用，并可能导致这些化合物的更合理设计，用于治疗以免疫反应紊乱、炎症和组织损伤为特征的疾病患者。

DESCRIPTION (provided by applicant): The overall object of this proposal is to determine biochemical and molecular mechanisms whereby cannabinoid acids without psychoactive activities modulate the function of cells (macrophages, synovial cells) which participate in initiation and propagation of joint tissue injury in patients with rheumatoid arthritis. The cannabinoid acids to be studied include ajulemic acid (AjA), and tetrahydrocannabinol-11 oic acid. These compounds do not alter behavior, are given by mouth, and do not injure gastric mucosa. Oral administration of AjA, a synthetic nonpsychoactive analog of the tetrahydrocannabinol (THC) carboxylic acid metabolite THC-11-oic acid, prevents joint cartilage and bone damage in an animal model of arthritis. Preliminary studies indicate that addition of cannabinoid acids to cells in vitro suppress gene expression of several inflammatory cytokines, and enhances apoptosis. Oral administration of AjA to humans attenuates IL-11beta production by activated monocytes. The main hypothesis of the proposal is that cannabinoid acids antagonize activation of the transcription factor NFkB due to and/or independent of activation of peroxisome proliferator activated receptor gamma (PPARy), leading to enhancement of apoptosis and downregulation of NFkB target genes (Il-1, IL-6, IL-8, COX-2). The role of eicosanoids in the actions of cannabinoid acids will be investigated also. Cells will be obtained from healthy volunteers, and patients with osteoarthritis and rheumatoid arthritis. Cannabinoid acids will be added to cells in vitro. Cells obtained from healthy volunteers before and after oral administration of AjA will be studied ex vivo. Experiments are designed to determine whether cannabinoid acids are bona fide ligands for PPARy and to investigate mechanisms by which cannabinoid acids alter NFkB signaling. Investigations will include use of gene transfection, western blotting, and immunomicroscopy. Completion of this proposal will provide a greater understanding of antiinflammatory and immunomodulatory effects of cannabinoid acids, and may lead to more rational design of these compounds for treatment of patients with diseases characterized by disordered immune responses, inflammation, and tissue injury.