A novel synthetic cannabinoid derivative inhibits inflammatory liver damage via negative cytokine regulation
A novel synthetic cannabinoid derivative inhibits inflammatory liver damage via negative cytokine regulation
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DOI：
10.1124/mol.64.6.1334
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发表时间：
2003-12-01
影响因子：
3.6
通讯作者：
Avraham, A
中科院分区：
文献类型：
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作者：
Lavon, I;Sheinin, T;Avraham, A
大麻素的治疗潜力以前已经描述了几种炎症性疾病，但大麻素抗炎特性的分子机制还没有得到很好的理解。在这项研究中，我们研究了一种新的合成大麻素，[（+）（6aS，10aS）-6，6-二甲基-3-（1，1-二甲基庚基）-1-羟基-9（1H-咪唑-2-基硫基甲基）-6a，7，10，10a-四氢-6H-二苯并[B，d]吡喃（PRS-211，092）的作用机制，该化合物没有精神作用，但具有免疫调节特性。PRS-211，092治疗可显著降低伴刀豆球蛋白A诱导的小鼠肝损伤，并伴有：1）促进在该模型中起保护作用的白细胞介素（IL）-6和IL-10的早期基因表达; 2）诱导细胞因子信号传导抑制因子的早期基因表达（SOCS-1和3），然后3）抑制几种促炎介质，包括IL-2、单核细胞趋化蛋白-1（MCP-1）、IL-1 β、干扰素-γ和肿瘤坏死因子α。基于这些结果，我们提出了PRS-211，092刺激IL-6、IL-10和SOCS蛋白表达的机制，这反过来又负调节促炎细胞因子的表达。在培养的T细胞中进一步证明了PRS-211，092的负调节，其中其抑制IL-2产生和活化T细胞活性的核因子。这些发现表明，这种大麻素衍生物是一种免疫调节剂，可以开发为治疗肝炎以及其他短期或长期炎症性疾病的潜在药物。
The therapeutic potential of cannabinoids has been described previously for several inflammatory diseases, but the molecular mechanisms underlying the anti-inflammatory properties of cannabinoids are not well understood. In this study, we investigated the mechanism of action of a novel synthetic cannabinoid, [(+)(6aS,10aS)-6,6-Dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-9(1H-imidazol-2-ylsulfanylmethyl]-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d] pyran (PRS-211,092) that has no psychotropic effects but exhibits immunomodulatory properties. Treatment with PRS-211,092 significantly decreased Concanavalin A-induced liver injury in mice that was accompanied by: 1) promotion of early gene expression of interleukin (IL)-6 and IL-10 that play a protective role in this model; 2) induction of early gene expression of the suppressors of cytokine signaling (SOCS-1 and 3), followed by 3) inhibition of several pro-inflammatory mediators, including IL-2, monocyte chemoattractant protein-1 (MCP-1), IL-1beta, interferon-gamma, and tumor necrosis factor alpha. Based on these results, we propose a mechanism by which PRS-211,092 stimulates the expression of IL-6, IL-10 and the SOCS proteins that, in turn, negatively regulates the expression of pro-inflammatory cytokines. Negative regulation by PRS-211,092 was further demonstrated in cultured T cells, where it inhibited IL-2 production and nuclear factor of activated T cells activity. These findings suggest that this cannabinoid derivative is an immunomodulator that could be developed as a potential drug for hepatitis as well as for other short- or long-term inflammatory diseases.