Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK

Abstract

AIMTo investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future.METHODSWe established the colitis model in C57BL/6 mice by replacing the animals’ water supply with 4% dextran sulfate sodium (DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the myeloperoxidase (MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase (p38MAPK) and its phosphorylated form (p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580 (SB), an inhibitor of p38, was investigated in parallel experiments, and the data were compared with those from intervention groups of WIN55 and SB alone or used together.RESULTSThe results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38MAPK was inhibited.CONCLUSIONThese results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38MAPK signaling pathway and the endogenous CB system.

Activation of cannabinoid 2 receptor relieves colonic hypermotility in a rat model of irritable bowel syndrome

“…Our data suggested the involvement of p38 MAPK signaling in CB2 receptor‐mediated regulation of intestinal motility in stress‐induced IBS. These results are in agreement with previous reports on the close association between CB2 receptors and p38 MAPK inhibition, suggesting that CB2 receptors are coupled to MAPK through G proteins and regulate MAPK phosphorylation . Our data are also in line with the finding that p38 MAPK is required for the production of IBS‐like symptoms .…”

“…One potential explanation may be that chronic stress directly regulates the colon ECS via the brain-gut axis through key alterations in the inhibition, suggesting that CB2 receptors are coupled to MAPK through G proteins and regulate MAPK phosphorylation. 29 Our data are also in line with the finding that p38 MAPK is required for the production of IBS-like symptoms. 30 Nitric oxide (NO), produced by nNOS, is a major GI inhibitory neurotransmitter.…”

Improvement of Inflammation through Antioxidant Pathway of Gardeniae Fructus 50% EtOH Extract (GE) from Acute Reflux Esophagitis Rats

“…MAPK signaling is associated with nuclear factor NF-κB, one of the transcription factors. In particular, the phosphorylation of p38 and ERK induces activation of NF-κB with many direct and indirect interactions [45,46]. Both GL and GH treatment groups showed significant results, indicating a role in reducing inflammatory factors (Figure 8).…”

Herbal medicinal products for inflammatory bowel disease: A focus on those assessed in double‐blind randomised controlled trials

“…Mouse model studies have shown an incremental therapeutic benefit of both cannabidiol and THC over sulfasalazine in reducing inflammation and functional symptoms (Jamontt, Molleman, Pertwee, & Parsons, ). A possible mechanism of action of the colonic anti‐inflammatory effect of CB receptor activation is the inhibition of p38‐mitogen‐activated protein kinase signalling, as shown in studies of the nonselective CB receptor agonist WIN55,212 using a murine model of dextran sulfate sodium‐induced colitis (Li et al, ; Feng, Li, Lin, Li, & Cao, ; Table ). A recent meta‐analysis of 34 animal studies reporting the effects of cannabinoid drugs on disease activity index (DAI) or myeloperoxidase activity in various models of mouse or rat colitis concluded that these drugs are beneficial in treating this kind of experimental disease, which warrants the undertaking of appropriate clinical trials (Couch, Maudslay, Doleman, Lund, & O'Sullivan, ).…”