期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 20, 页码 7895-7900出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0511232103
关键词
adenosine; ipopolysaccharide; tetrahydrocannabinol; thymidine; tumor necrosis factor-alpha
资金
- NHLBI NIH HHS [HL077707, R01 HL077707, R01 HL077707-02] Funding Source: Medline
- NIDA NIH HHS [R01 DA016967, R01 DA009155, DA09155, DA16967] Funding Source: Medline
- NINDS NIH HHS [NS041314, R01 NS041314] Funding Source: Medline
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.
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