A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Sumariwalla
Percy F
PF
Kennedy Institute of Rheumatology, Imperial College London, London, UK.
Gallily
Ruth
R
Tchilibon
Susanna
S
Fride
Ester
E
Mechoulam
Raphael
R
Feldmann
Marc
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000473:pathology* / Q000503:physiopathology*; D002185:Cannabidiol / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D007596:Joints / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D003509:Cyclohexanecarboxylic Acids; C483300:HU 320; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D002185:Cannabidiol