β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway

Abstract

Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-␥ (PPAR␥) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-␤-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the antiinflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPAR␥. Oral treatment with BCP reduced disease activity, colonic macro-and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-␣, IL-1␤, interferon-␥, and keratinocyte-derived chemokine. Inflammatory bowel diseases (IBDs) are a group of chronic diseases that affect the gastrointestinal tract and have been mainly subdivided as ulcerative colitis and Crohn's disease. 1 The IBDs are characterized by a strong leukocyte activation and infiltration into the intestinal tissues, the release of proinflammatory cytokines 2 and enzymes, and the formation of reactive oxygen species. All of these events can induce an extensive and unbalanced activation of the mucosal immune system, driven by the commensal flora. 3 Recent evidence suggests a role for the cannabinoid system in IBD regulation. Cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed in normal human colon 4,5 and are up-regulated in IBD colonic tissue. In addition, an enhanced level of endocannabinoids was found in biopsy specimens from patients with ulcerative colitis. 5 It is thought that CB1 activation results in a decrease of intestinal hypermotility and hypersecretion, whereas the activation of CB2 results in the inhibition of proinflammatory mediators. In addition, both CB2 and CB1 knockout mice are more susceptible to the development of experimental colitis, and the activation of these receptors is extremely important for the abrogation of intestinal inflammation. 6 The role of CB2, however, is directly involved with innate immune system, because CB2 is primarily expressed in immune cells, such as macrophages, CD4 ϩ and CD8 ϩ T cells, monocytes, and polymorphonuclear neutro-

Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis

“…juresianum, is completely inactive. This finding is somewhat unexpected as E-caryophyllene has been reported to exert anti-inflammatory effects by activating cannabinoid CB2 receptors (Bento et al, 2011;Medeiros et al, 2007) and endogenous and synthetic cannabinoids have been reported to decrease inflammation in animal models of arthritis (Sumariwalla et al, 2004) and to inhibit IL-1-induced NO production in bovine chondrocytes (Mbvundula et al, 2005).…”

β‐Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice

“…Pathologically over-activated macrophages, as seen in alcoholic-, and in non-alcoholic fatty liver disease, may further aggravate tissue injury and inflammation, leading to liver failure. As BCP has been proposed to protect the colonic mucosa against dextran sulfate-induced colitis (Cho et al, 2007;Bento et al, 2011), it is possible that BCP could exert similar protection against ethanol-induced mucosal damage and thereby also attenuate endotoxin translocation from the gut to the portal circulation (Bode et al, 1987).…”

“…This makes BCP a promising food-derived agent that may be exploited therapeutically to treat various inflammatory diseases (Gertsch et al, 2008). BCP has been reported to exert protective effects in experimental animal models of inflammatory pain (Gertsch et al, 2008), kidney injury (Horvath et al, 2012b), ischaemic stroke (Choi et al, 2013), Parkinson's disease (Ojha et al, 2016), toxic hepatitis (D-galactosamine-and endotoxin-induced) (Cho et al, 2015), experimental liver fibrosis (Mahmoud et al, 2014) and colitis (Bento et al, 2011). BCP has been also proposed recently, to have anti-addictive potential (Al Mansouri et al, 2014).…”

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…and absent in CB 2 À/À mice [36,61]. In one study, AM630 seemed to exacerbate TNBS-induced colitis [61], but this was not consistent over all measured parameters and was not confirmed by two other studies using AM630 in studies of TNBS-induced and DSS-induced colitis [57,65].…”