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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression
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Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression

机译：大麻二酚对平衡核苷转运蛋白的抑制作用：大麻素免疫抑制的机制

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摘要

The plant-derived cannabinoids Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) both have immunosuppressive effects; although some effects of THC are mediated by the CB2 receptor, CB2 binds CBD weakly. in examining the effects of THC and CBD on microglial proliferation, we found that these compounds potently inhibit [H-3]thymidine incorporation into a murine microglial cell line with no effect on cell cycle. Treatment with THC and CBD decreased [H-3]thymidine uptake into microglia, with IC50 values that match inhibition of [H-3]thymidine incorporation into DNA. CBD and, less potently, THC decreased uptake of [H-3]adenosine to a similar extent as [H-3]thymidine in both murine microglia and RAW264.7 macrophages. Binding studies confirm that CBD binds to the equilibrative nucleoside transporter 1 with a K-i < 250 nM. Because adenosine agonists have antiinflammatory effects, and because uptake of adenosine is a primary mechanism of terminating adenosine signaling, we tested the hypothesis that CBD is immunosuppressive because it enhances endogenous adenosine signaling. In vivo treatment with a low dose of CBD decreases TNF alpha production in lipopolysaccharide-treated mice; this effect is reversed with an A(2A) adenosine receptor antagonist and abolished in A(2A) receptor knockout mice. These studies demonstrate that CBD has the ability to enhance adenosine signaling through inhibition of uptake and provide a non-cannabinoid receptor mechanism by which CBD can decrease inflammation.
机译：植物来源的大麻素Delta（9）-四氢大麻酚（THC）和大麻二酚（CBD）均具有免疫抑制作用。尽管THC的某些作用是由CB2受体介导的，但CB2与CBD的结合较弱。在检查THC和CBD对小胶质细胞增殖的影响时，我们发现这些化合物有效抑制[H-3]胸苷掺入鼠小胶质细胞系，而对细胞周期没有影响。 THC和CBD处理可降低[H-3]胸腺嘧啶对小胶质细胞的吸收，IC50值与[H-3]胸苷对掺入DNA的抑制作用相匹配。在鼠小胶质细胞和RAW264.7巨噬细胞中，CBD和不太有效的THC降低[H-3]腺苷的吸收程度与[H-3]胸苷相似。结合研究证实，CBD以＜250 nM的K-i与平衡的核苷转运蛋白1结合。因为腺苷激动剂具有抗炎作用，并且由于腺苷摄取是终止腺苷信号传导的主要机制，所以我们测试了CBD具有免疫抑制作用的假说，因为它增强了内源性腺苷信号传导。在脂多糖治疗的小鼠中，低剂量的CBD体内治疗可降低TNFα的产生；这种作用与A（2A）腺苷受体拮抗剂逆转，在A（2A）受体基因敲除小鼠中被废除。这些研究表明，CBD具有通过抑制摄取增强腺苷信号传导的能力，并提供了非大麻素受体机制，CBD可以通过该机制减少炎症。

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