Involvement of cannabinoid-1 and cannabinoid-2 receptors in septic ileus

Li, Y.‐y.; Ni, Jing; Chen, C.‐j.; Lv, Shuai; Chai, Shangyu; Wu, Rui; Yüce, B.; Storr, Martin

doi:10.1111/j.1365-2982.2009.01419.x

Cited by 37 publications

(44 citation statements)

References 45 publications

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“…Since then, it has been brought into focus due to its huge potential in regulating gastrointestinal inflammation, abdominal pain, diarrhea, etc [7]. WIN55-212-2(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo(1,2,3-de)-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN55) is a typical cannabinoid receptor agonist and can activate ECS via acting on the Gi/o coupled membrane receptors: cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), the two main typical cannabinoid receptors[8,9]. WIN55 has been reported as beneficial in treating gastrointestinal inflammatory disorders; albeit, its pharmacological mechanism has not been demonstrated clearly[10,11].…”

Section: Introductionmentioning

confidence: 99%

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

Feng¹,

Li²,

Lin³

et al. 2016

WJG

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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.

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Section: Introductionmentioning

confidence: 99%

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

Feng¹,

Li²,

Lin³

et al. 2016

WJG

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“…In addition, the anti-inflammatory potential of cannabinoids has been of interest since their discovery in mammalians [16]. Enhancement of cannabinoid signaling and increased expression of CB1/CB2 receptors and/or endocannabinoid levels were observed following inflammatory stimuli in animals and in intestinal biopsies from patients with gut inflammatory disorders [21]–[23]. Several groups also showed that cannabinoids had exerted anti-inflammatory actions in the gut by activating CB1 receptor, and that the mechanism of action had involved inhibition of chemokines and proinflammatory cytokines, which were mainly released from macrophage and mast cells [24], [25].…”

Section: Introductionmentioning

confidence: 99%

The Dual Effect of Cannabinoid Receptor-1 Deficiency on the Murine Postoperative Ileus

Cao

Goetz

et al. 2013

PLoS ONE

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IntroductionIntestinal inflammatory responses play a critical role in the pathogenesis of postoperative ileus (POI). As cannabinoid receptor-1 (CB1) is involved in inhibiting gastrointestinal (GI) motility and anti-inflammation, we aimed to explore its contribution to POI.MethodsExperimental POI was induced in adult female CB1-deficient (CB1–/–) mice and wild-type littermates (C57BL/6N) by standardized small bowel manipulation. Twenty-four hours after surgery, GI transit was assessed by charcoal transport. FITC avidin, F4/80, and myeloperoxidase immunohistochemistry techniques were used to evaluate the inflammatory response in the muscularis of ileum and colon. Expressions of p38MAPK and its phosphorylated form (pp38) in the intestine were determined. Plasma levels of proinflammatory cytokines and chemokines were measured by ELISA as well.ResultsPOI was characterized by decreased GI transit (p<0.01) and accompanied by a marked intestinal and systematic inflammatory response in wild-type and CB1–/– mice. Increased numbers of inflammatory cells, including macrophages, neutrophils, and mast cells were observed in the muscularis of ileum and colon (p<0.01, or p<0.05). Plasma levels of interleukin-6 (IL-6), cytokine-induced neutrophil chemoattractant-1 (CINC-1/KC), and monocyte chemoattractant protein-1 (MCP-1) were elevated (p<0.01, or p<0.05). Expression of p38 and pp38 increased in the intestine (p<0.01, or p<0.05). CB1–/– mice showed an increased inflammatory response during POI, especially the systemic inflammatory markers, such as IL-6, KC, CINC1, and pp38 expression were increased as compared to those in WT mice (p<0.05).ConclusionsIntestinal motility was inhibited during POI. In this condition, inhibition of motility did not seem to be altered by the absence of CB1 receptors, however, an increased inflammatory response was observed in CB1–/– mice. Hence, CB1 receptor activation rather than inhibition may reduce the inflammatory response in POI, which has a remote potential to relate into reduced inhibition of intestinal motility during POI.

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“…13 Furthermore, Mk2 deletion interferes with a variety of inflammatory reactions, which include inflammation in the pancreas, 14,15 neurons, 16 and joints. 17 The role of cannabinoids (CBs) in modulating gastrointestinal (GI) inflammation has attracted much research interest in recent years, 18,19 and investigators have presented solid evidences of the presence of CB receptors, including CB1 and CB2 receptors in the GI tract. [19][20][21][22] Specifically, the murine model colitis induced by different chemicals is generally more severe in CB1 knockout mice than that in wild-type (WT) mice, and pretreatment of WT mice with CB1 receptor antagonists prompts an upregulated inflammatory response in various models, whereas the administration of CB1 receptor agonists resulted in reduced inflammatory response.…”

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confidence: 99%

Inhibition of p38/Mk2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis

Yuece

Cao

et al. 2013

Laboratory Investigation

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P38/Mk2 (mitogen-activated protein kinase (MAPK)-activated protein kinase-2, also known as MAKAP kinase-2) is a member of the mitogen-activated protein kinases (MAPKs) family, and participates in inflammatory responses directly or indirectly. WIN55, 212-2 (WIN55) is a synthetic non-selective agonist of cannabinoid (CB) receptors with remarkable antiinflammatory properties. This study was to explore the roles of WIN55 and p38/Mk2 signaling pathway in dextran sodium sulfate (DSS)-induced mouse colitis and ascertain their anti-inflammatory mechanisms. Colitis was induced in C57BL Mk2 gene homozygous deletion (Mk2 À / À ) and wild-type mice by replacing the drinking water with 4% DSS solution for 7 days. DSS-treated mice developed bloody stool, weight loss, and eye-visible multiple bleeding ulcers on colon mucosa. The mRNA expressions levels of TNF-a and IL-6, as well as the protein levels of p38 and its phosphorylated form (p-p38), were upregulated in the colon. The plasma levels of TNF-a, IL-6, cytokine-induced neutrophil chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), and lung myeloperoxidase (MPO) activities were raised; however, all these changes were less severe in Mk2 À / À mice. After WIN55 intervention, the Mk2 À / À mice recovered faster and better from the induced colitis than their wild-type counterparts. The results indicate that the Mk2 homozygous deletion in mice impedes the induction of experimental colitis by DSS, confirming the notion that p38/Mk2 is involved in this inflammatory response. WIN55 protects mice against DSS-induced colitis, in particular when the p38/Mk2 pathway is obstructed, implying that the activation of CB system, together with blocking of p38/Mk2 pathway, serves as a potential drug target for colitis treatment.

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Involvement of cannabinoid-1 and cannabinoid-2 receptors in septic ileus

Cited by 37 publications

References 45 publications

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

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

The Dual Effect of Cannabinoid Receptor-1 Deficiency on the Murine Postoperative Ileus

Inhibition of p38/Mk2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis

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