Abstract
BackgroundNon-psychotropic atypical cannabinoids have therapeutic potential in a variety of inflammatory conditions including those of the gastrointestinal tract. Here we examined the effects of the atypical cannabinoid abnormal cannabidiol (Abn-CBD) on wound healing, inflammatory cell recruitment and colitis in mice.MethodsColitis was induced in CD1 mice by a single intrarectal administration of trinitrobenzene sulfonic acid (TNBS, 4 mg/100 μl in 30 % ethanol) and Abn-CBD and/or the antagonists O-1918 (Abd-CBD), AM251 (CB1 receptor) and AM630 (CB2 receptor), were administered intraperitoneally (all 5 mg/kg, twice daily for 3 days). The degree of colitis was assessed macro- and microscopically and tissue myeloperoxidase activity was determined. The effects of Abn-CBD on wound healing of endothelial and epithelial cells (LoVo) were assessed in a scratch injury assay. Human neutrophils were employed in Transwell assays or perfused over human umbilical vein endothelial cells (HUVEC) to study the effect of Abn-CBD on neutrophil accumulation and transmigration.ResultsTNBS-induced colitis was attenuated by treatment with Abn-CBD. Histological, macroscopic colitis scores and tissue myeloperoxidase activity were significantly reduced. These effects were inhibited by O-1918, but not by AM630, and only in part by AM251. Wound healing of both HUVEC and LoVo cells was enhanced by Abn-CBD. Abn-CBD inhibited neutrophil migration towards IL-8, and dose-dependently inhibited accumulation of neutrophils on HUVEC.ConclusionsAbn-CBD is protective against TNBS-induced colitis, promotes wound healing of endothelial and epithelial cells and inhibits neutrophil accumulation on HUVEC monolayers. Thus, the atypical cannabinoid Abn-CBD represents a novel potential therapeutic in the treatment of intestinal inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12950-016-0129-0) contains supplementary material, which is available to authorized users.
Highlights
Non-psychotropic atypical cannabinoids have therapeutic potential in a variety of inflammatory conditions including those of the gastrointestinal tract
It has been demonstrated that CBD and O1602 protect against experimentally induced colitis in mice, but their mechanisms of action requires further investigation, notably, as the protective properties of O-1602 are observed in mice lacking the GPR55 gene [8, 9]
MPO activity was significantly higher in colitic mice compared to controls and abnormal cannabidiol (Abn-CBD) treated colitic mice (Fig. 1b), indicating that Abn-CBD either inhibits inflammatory neutrophil recruitment or accelerates clearance of neutrophils from the tissue, reducing the inflammatory response
Summary
Non-psychotropic atypical cannabinoids have therapeutic potential in a variety of inflammatory conditions including those of the gastrointestinal tract. Using CBD as the prototype, synthetic analogs have been developed such as the regio-isomer abnormal cannabidiol (Abn-CBD) and it’s close relative O-1602 These ‘atypical’ cannabinoids lack significant binding affinity to cannabinoid receptors, but act on novel targets such as the orphan receptor GPR55 [6, 7]. It has been demonstrated that CBD and O1602 protect against experimentally induced colitis in mice, but their mechanisms of action requires further investigation, notably, as the protective properties of O-1602 are observed in mice lacking the GPR55 gene [8, 9] They might be conferred by GPR18, another target of O-1602 and the putative receptor of Abn-CBD [10]. While studies have examined the vasodilatory and neuroprotective effects of Abn-CBD [7, 11,12,13], its potential role in the modulation of gastrointestinal inflammation has not been examined
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