Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A4.
Ajulemic acid (AjA), a synthetic nonpsychoactive cannabinoid, and lipoxin A(4) (LXA(4)), an eicosanoid formed from sequential actions of 5- and 15-lipoxygenases (LOX), facilitate resolution of inflammation. The purpose of this study was to determine whether the ability of AjA to limit the progress of inflammation might relate to an increase in LXA(4), a known anti-inflammatory and proresolving mediator. Addition of AjA (0-30 microM) in vitro to human blood and synovial cells increased production of LXA(4) (ELISA) 2- to 5-fold. Administration of AjA to mice with peritonitis resulted in a 25-75% reduction of cells invading the peritoneum, and a 7-fold increase in LXA(4) identified by mass spectrometry. Blockade of 12/15 LOX, which leads to LXA(4) synthesis via 15-HETE production, reduced (>90%) the ability of AjA to enhance production of LXA(4) in vitro. These results suggest that AjA and other agents that increase endogenous compounds that facilitate resolution of inflammation may be useful for conditions characterized by inflammation and tissue injury.
Zurier
Robert B
RB
University of Massachusetts Medical School, Division of Rheumatology, 55 Lake Ave, Worcester, MA 01655, USA. robert.zurier@umassmed.edu
Sun
Yee-Ping
YP
George
Kerri L
KL
Stebulis
Judith A
JA
Rossetti
Ronald G
RG
Skulas
Ann
A
Judge
Erica
E
Serhan
Charles N
CN
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology*; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D044045:Lipoxins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy
D000893:Anti-Inflammatory Agents; D002186:Cannabinoids; D044045:Lipoxins; C040527:lipoxin A4; D013759:Dronabinol; C471849:lenabasum