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Journal of Inflammation
Published in: Journal of Inflammation 1/2016

Open Access 01-12-2016 | Research

Abnormal cannabidiol attenuates experimental colitis in mice, promotes wound healing and inhibits neutrophil recruitment

Authors: Regina M. Krohn, Sean A. Parsons, Jakub Fichna, Kamala D. Patel, Robin M. Yates, Keith A. Sharkey, Martin A. Storr

Published in: Journal of Inflammation | Issue 1/2016

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Abstract

Background

Non-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.

Methods

Colitis 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.

Results

TNBS-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.

Conclusions

Abn-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.
Appendix
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Literature
1.
Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006;105:1–25.CrossRefPubMed
2.
3.
Izzo AA, Coutts AA. Cannabinoids and the digestive tract. Handb Exp Pharmacol. 2005:573-598. ISSN: 0171-2004.
4.
5.
Booz GW. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med. 2011;51:1054–61.CrossRefPubMedPubMedCentral
6.
Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152:1092–101.CrossRefPubMedPubMedCentral
7.
Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A. 1999;96:14136–41.CrossRefPubMedPubMedCentral
8.
Borrelli F, Aviello G, Romano B, Orlando P, Capasso R, Maiello F, Guadagno F, Petrosino S, Capasso F, Di Marzo V, Izzo AA. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. J Mol Med (Berl). 2009;87:1111–21.CrossRef
9.
Schicho R, Bashashati M, Bawa M, McHugh D, Saur D, Hu HM, Zimmer A, Lutz B, Mackie K, Bradshaw HB, et al. The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment. Inflamm Bowel Dis. 2011;17:1651–64.CrossRefPubMed
10.
McHugh D, Hu S, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw H. N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci. 2010;11:44.CrossRefPubMedPubMedCentral
11.
Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels DA, Riddick M, Dowell S, Staton PC, Green P, et al. The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. Br J Pharmacol. 2007;152:825–31.CrossRefPubMedPubMedCentral
12.
Su EN, Kelly ME, Cringle SJ, Yu DY. Role of Endothelium in Abnormal Cannabidiol-Induced Vasoactivity in Retinal Arterioles. Invest Ophthalmol Vis Sci. 2015;56:4029–37.CrossRefPubMed
13.
Kreutz S, Koch M, Bottger C, Ghadban C, Korf HW, Dehghani F. 2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors on microglial cells. Glia. 2009;57:286–94.CrossRefPubMed
14.
Frøslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal Healing in Inflammatory Bowel Disease: Results From a Norwegian Population-Based Cohort. Gastroenterology. 2007;133:412–22.CrossRefPubMed
15.
Seidelin JB, Coskun M, Nielsen OH. Mucosal healing in ulcerative colitis: pathophysiology and pharmacology. Adv Clin Chem. 2013;59:101–23.CrossRefPubMed
16.
Engel M, Kellerman C, Rau T, Burnat G, Hahn E, Konturek P. Ulcerative colitis in AKR mice is attenuated by intraperitoneally administered anandamide. Acta Physiol Pol. 2008;59:673.
17.
Storr MA, Keenan CM, Zhang H, Patel KD, Makriyannis A, Sharkey KA. Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis. Inflamm Bowel Dis. 2009;15:1678–85.CrossRefPubMed
18.
Krawisz JE, Sharon P, Stenson WF. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology. 1984;87:1344–50.PubMed
19.
Kimball ES, Wallace NH, Schneider CR, D’Andrea MR, Hornby PJ. Vanilloid receptor 1 antagonists attenuate disease severity in dextran sulphate sodium-induced colitis in mice. Neurogastroenterol Motil. 2004;16:811–8.CrossRefPubMed
20.
Cuvelier SL, Patel KD. Shear-dependent eosinophil transmigration on interleukin 4-stimulated endothelial cells: a role for endothelium-associated eotaxin-3. J Exp Med. 2001;194:1699–709.CrossRefPubMedPubMedCentral
21.
Zimmerman GA, McIntyre TM, Prescott SM. Thrombin stimulates the adherence of neutrophils to human endothelial cells in vitro. J Clin Invest. 1985;76:2235–46.CrossRefPubMedPubMedCentral
22.
Aepfelbacher M, Essler M, Huber E, Sugai M, Weber PC. Bacterial toxins block endothelial wound repair. Evidence that Rho GTPases control cytoskeletal rearrangements in migrating endothelial cells. Arterioscler Thromb Vasc Biol. 1997;17:1623–9.CrossRefPubMed
23.
Offertaler L, Mo FM, Batkai S, Liu J, Begg M, Razdan RK, Martin BR, Bukoski RD, Kunos G. Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol. 2003;63:699–705.CrossRefPubMed
24.
25.
Izzo RS, Witkon K, Chen AI, Hadjiyane C, Weinstein MI, Pellecchia C. Interleukin-8 and neutrophil markers in colonic mucosa from patients with ulcerative colitis. Am J Gastroenterol. 1992;87:1447–52.PubMed
26.
Carlson M, Raab Y, Seveus L, Xu S, Hallgren R, Venge P. Human neutrophil lipocalin is a unique marker of neutrophil inflammation in ulcerative colitis and proctitis. Gut. 2002;50:501–6.CrossRefPubMedPubMedCentral
27.
Foell D, Kucharzik T, Kraft M, Vogl T, Sorg C, Domschke W, Roth J. Neutrophil derived human S100A12 (EN-RAGE) is strongly expressed during chronic active inflammatory bowel disease. Gut. 2003;52:847–53.CrossRefPubMedPubMedCentral
28.
Lampinen M, Sangfelt P, Taha Y, Carlson M. Accumulation, activation, and survival of neutrophils in ulcerative colitis: regulation by locally produced factors in the colon and impact of steroid treatment. Int J Colorectal Dis. 2008;23:939–46.CrossRefPubMed
29.
Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7:678–89.CrossRefPubMed
30.
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial Function and Dysfunction: Testing and Clinical Relevance. Circulation. 2007;115:1285–95.PubMed
31.
32.
Jager S, Stange EF, Wehkamp J. Inflammatory bowel disease: an impaired barrier disease. Langenbecks Arch Surg. 2013;398:1–12.CrossRefPubMed
33.
Wright K, Rooney N, Feeney M, Tate J, Robertson D, Welham M, Ward S. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology. 2005;129:437–53.CrossRefPubMed
34.
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW, Kaplan GG. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54. e42; quiz e30.CrossRefPubMed
35.
Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126:21–38.CrossRefPubMed
36.
Izzo AA, Camilleri M. Cannabinoids in intestinal inflammation and cancer. Pharmacol Res. 2009;60:117–25.CrossRefPubMed
37.
Pacher P, Mukhopadhyay P, Mohanraj R, Godlewski G, Batkai S, Kunos G. Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. Hypertension. 2008;52:601–7.CrossRefPubMedPubMedCentral
38.
39.
D’Argenio G, Valenti M, Scaglione G, Cosenza V, Sorrentini I, Di Marzo V. Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J. 2006;20:568–70.PubMed
40.
Gatley SJ, Lan R, Pyatt B, Gifford AN, Volkow ND, Makriyannis A. Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors. Life Sci. 1997;61:PL 191–197.CrossRef
41.
Henstridge CM, Balenga NA, Schroder R, Kargl JK, Platzer W, Martini L, Arthur S, Penman J, Whistler JL, Kostenis E, et al. GPR55 ligands promote receptor coupling to multiple signalling pathways. Br J Pharmacol. 2010;160:604–14.CrossRefPubMedPubMedCentral
42.
Davignon J, Ganz P. Role of Endothelial Dysfunction in Atherosclerosis. Circulation. 2004;109:III-27–32.CrossRef
43.
Chin AC, Parkos CA. Neutrophil transepithelial migration and epithelial barrier function in IBD: potential targets for inhibiting neutrophil trafficking. Ann N Y Acad Sci. 2006;1072:276–87.CrossRefPubMed
44.
Kucharzik T, Walsh SV, Chen J, Parkos CA, Nusrat A. Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins. Am J Pathol. 2001;159:2001–9.CrossRefPubMedPubMedCentral
45.
46.
Daig R, Andus T, Aschenbrenner E, Falk W, Scholmerich J, Gross V. Increased interleukin 8 expression in the colon mucosa of patients with inflammatory bowel disease. Gut. 1996;38:216–22.CrossRefPubMedPubMedCentral
47.
Izutani R, Loh EY, Reinecker HC, Ohno Y, Fusunyan RD, Lichtenstein GR, Rombeau JL, Macdermott RP. Increased expression of interleukin-8 mRNA in ulcerative colitis and Crohn’s disease mucosa and epithelial cells. Inflamm Bowel Dis. 1995;1:37–47.PubMed
48.
Johnson Z, Proudfoot AE, Handel TM. Interaction of chemokines and glycosaminoglycans: a new twist in the regulation of chemokine function with opportunities for therapeutic intervention. Cytokine Growth Factor Rev. 2005;16:625–36.CrossRefPubMed
49.
Shaw SK, Ma S, Kim MB, Rao RM, Hartman CU, Froio RM, Yang L, Jones T, Liu Y, Nusrat A, et al. Coordinated redistribution of leukocyte LFA-1 and endothelial cell ICAM-1 accompany neutrophil transmigration. J Exp Med. 2004;200:1571–80.CrossRefPubMedPubMedCentral
50.
McHugh D, Tanner C, Mechoulam R, Pertwee RG, Ross RA. Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Mol Pharmacol. 2008;73:441–50.CrossRefPubMed
Metadata
Title
Abnormal cannabidiol attenuates experimental colitis in mice, promotes wound healing and inhibits neutrophil recruitment
Authors
Regina M. Krohn
Sean A. Parsons
Jakub Fichna
Kamala D. Patel
Robin M. Yates
Keith A. Sharkey
Martin A. Storr
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Inflammation / Issue 1/2016
Electronic ISSN: 1476-9255
DOI
https://doi.org/10.1186/s12950-016-0129-0

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