Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH)

Abstract

Background and aims Pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBD) is currently one of the biggest challenge in the field of gastroenterology. Available therapies are mostly limited to overcoming the symptoms, but not the cause of the disease. Recently, the endocannabinoid system has been proposed as a novel target in the treatment of IBD. Here we aimed to assess the anti-inflammatory action of the novel fatty acid amide hydrolase (FAAH) inhibitor PF-3845 and its effect on the endocannabinoid and related lipid metabolism during the course of experimental colitis. Methods We used two models of experimental colitis in mice (TNBS- and DSS-induced) and additionally, we employed LC/MS/MS spectrometry to determine the changes in biolipid levels in the mouse colon during inflammation. Results We showed that the FAAH inhibitor PF-3845 reduced experimental TNBS-induced colitis in mice and its anti-inflammatory action is associated with altering the levels of selected biolipids (arachidonic and oleic acid derivatives, prostaglandins and biolipids containing glycine in the mouse colon). Conclusions We show that FAAH is a promising pharmacological target and the FAAH-dependent biolipids play a major role in colitis. Our results highlight and promote therapeutic strategy based on targeting FAAH-dependent metabolic pathways in order to alleviate intestinal inflammation.

Encenicline, an 7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

“…The method described by Sałaga et al (2014) was used to quantify the myeloperoxidase (MPO) activity, which is an indicator of granulocyte infiltration (Pulli et al, 2013). Briefly, 1-cm segments of colon were weighed and homogenized in hexadecyltrimethylammonium bromide buffer (0.5% in 50 mM potassium phosphate buffer, pH 6.0; 1:20 w/v), afterward, the homogenate was centrifuged (15 minutes, 13,200g, 4°C).…”

Attenuation of Cystitis and Pain Sensation in Mice Lacking Fatty Acid Amide Hydrolase

“…FAAH KO mice also displayed decreased severity of experimental arthritis and colitis (Storr et al, 2008; Kinsey et al, 2011). Similarly, treatment with the FAAH inhibitors (D’Argenio et al, 2006; Storr et al, 2008; Sałaga et al, 2014) attenuated the severity of experimental colitis (Massa et al, 2004; D'Argenio et al, 2006; Storr et al, 2008; 2009; Salaga et al, 2014a, b). The anti-inflammatory effects observed in FAAH KO mice were primarily mediated by CB2 (Lichtman et al, 2004; Storr et al, 2008; Naidu et al, 2010; Kinsey et al, 2011).…”

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

“…Colitis produced by 2,4-dinitrobenzene sulphonic acid (DNBS) or by dextran sulphate sodium is more severe in mice treated with rimonabant or in mice lacking CB 1 receptors and less severe in FAAH À/À mice than in FAAH þ/þ animals (Massa et al 2004). A partial reduction of colitis following FAAH inhibition either with URB597, with PF-3845 or with a novel compound (compound 39) is seen in the 2,4,6-trinitrobenzene sulphonic acid (TNBS) model (Storr et al 2008;Andrzejak et al 2011;Sałaga et al 2014). A similar result was seen with JZL184, an effect blocked by both rimonabant and AM630 (Alhouayek et al 2011).…”