Faculty Collaboration Database

Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 2006 May 16;103(20):7895-900

Date

05/05/2006

Pubmed ID

16672367

Pubmed Central ID

PMC1472541

DOI

10.1073/pnas.0511232103

Scopus ID

2-s2.0-33646734889 (requires institutional sign-in at Scopus site)   376 Citations

Abstract

The plant-derived cannabinoids delta9-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 [3H]thymidine incorporation into a murine microglial cell line with no effect on cell cycle. Treatment with THC and CBD decreased [3H]thymidine uptake into microglia, with IC50 values that match inhibition of [3H]thymidine incorporation into DNA. CBD and, less potently, THC decreased uptake of [3H]adenosine to a similar extent as [3H]thymidine in both murine microglia and RAW264.7 macrophages. Binding studies confirm that CBD binds to the equilibrative nucleoside transporter 1 with a Ki < 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 TNFalpha production in lipopolysaccharide-treated mice; this effect is reversed with an A2A adenosine receptor antagonist and abolished in A2A 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.

Author List

Carrier EJ, Auchampach JA, Hillard CJ

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine
Animals
Cannabidiol
Cell Line
Cell Proliferation
DNA
Dronabinol
Equilibrative Nucleoside Transporter 1
Lipopolysaccharides
Male
Mice
Mice, Inbred C57BL
Microglia
Nucleoside Transport Proteins
Piperidines
Psychotropic Drugs
Pyrazoles
Thymidine
Tumor Necrosis Factor-alpha