Sumariwalla Percy F, Gallily Ruth, Tchilibon Susanna, Fride Ester, Mechoulam Raphael, Feldmann Marc
Kennedy Institute of Rheumatology, Imperial College London, London, UK.
Arthritis Rheum. 2004 Mar;50(3):985-98. doi: 10.1002/art.20050.
To explore the antiarthritic potential of a novel synthetic cannabinoid acid, Hebrew University-320 (HU-320), in the DBA/1 mouse model of arthritis, and to investigate in vitro antiinflammatory and immunosuppressive effects of HU-320 on macrophages and lymphocytes.
DBA/1 mice were immunized with bovine type II collagen (CII) to induce arthritis and then injected intraperitoneally daily with HU-320. The effects of treatment on arthritic changes in hind feet were assessed clinically and histologically, and draining lymph node responses to CII were assayed. Murine splenic and human blood lymphocytes were cultured to study the effect of HU-320 on polyclonal mitogenic stimulation. Macrophage cultures were set up to evaluate in vitro effects of HU-320 on production of tumor necrosis factor alpha (TNF alpha) and reactive oxygen intermediates (ROIs). The effect of HU-320 administration on lipopolysaccharide-induced serum TNF levels was assayed using C57BL/6 mice. Bioactive TNF production was measured using BALB/c clone 7 target cells. Evaluation of HU-320 psychoactivity was performed using established laboratory tests on Sabra mice.
Systemic daily administration of 1 and 2 mg/kg HU-320 ameliorated established CII-induced arthritis. Hind foot joints of treated mice were protected from pathologic damage. CII-specific and polyclonal responses of murine and human lymphocytes were down-modulated. HU-320 inhibited production of TNF from mouse macrophages and of ROIs from RAW 264.7 cells and suppressed the rise in serum TNF level following endotoxin challenge. HU-320 administration yielded no adverse psychotropic effects in mice.
Our studies show that the novel synthetic cannabinoid acid HU-320 has strong antiinflammatory and immunosuppressive properties while demonstrating no psychoactive effects. The profound suppressive effects on cellular immune responses and on the production of proinflammatory mediators all indicate its usefulness as a novel nonpsychoactive, synthetic antiinflammatory product.
在DBA/1小鼠关节炎模型中探究新型合成大麻酸希伯来大学-320（HU-320）的抗关节炎潜力，并研究HU-320对巨噬细胞和淋巴细胞的体外抗炎及免疫抑制作用。
用牛II型胶原（CII）免疫DBA/1小鼠以诱导关节炎，然后每天腹腔注射HU-320。临床和组织学评估治疗对后足关节炎症变化的影响，并检测引流淋巴结对CII的反应。培养小鼠脾淋巴细胞和人血淋巴细胞，以研究HU-320对多克隆有丝分裂原刺激的影响。建立巨噬细胞培养体系，以评估HU-320对肿瘤坏死因子α（TNFα）和活性氧中间体（ROIs）产生的体外作用。使用C57BL/6小鼠检测HU-320给药对脂多糖诱导的血清TNF水平的影响。使用BALB/c克隆7靶细胞测量生物活性TNF的产生。使用既定的实验室检测方法对Sabra小鼠进行HU-320精神活性评估。
每天全身给予1和2mg/kg的HU-320可改善已建立的CII诱导的关节炎。治疗小鼠的后足关节免受病理损伤。小鼠和人淋巴细胞的CII特异性和多克隆反应受到下调。HU-320抑制小鼠巨噬细胞产生TNF以及RAW 264.7细胞产生ROIs，并抑制内毒素攻击后血清TNF水平的升高。给予HU-320对小鼠没有产生不良精神作用。
我们的研究表明，新型合成大麻酸HU-320具有强大的抗炎和免疫抑制特性，同时没有精神活性作用。对细胞免疫反应和促炎介质产生的显著抑制作用均表明其作为一种新型非精神活性合成抗炎产品的有用性。
