MAGL inhibition modulates gastric secretion and motility following NSAID exposure in mice

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are common analgesic drugs that also cause well-known, negative gastrointestinal (GI) side effects. The physiological mechanism(s) of NSAID-induced GI damage are unclear and are likely due to multiple causes. The most studied contributing mechanisms are increased gastric acid secretion and increased gastric motility. The present study was designed to determine which ulcerogenic effects of the NSAID diclofenac sodium are reversed by blocking the endocannabinoid catabolic enzyme monoacylglycerol lipase (MAGL). Both male and female mice were used to identify possible sex differences. We hypothesized that the MAGL inhibitor JZL184 would attenuate diclofenac-induced increases in both gastric acid secretion and gastric motility. Diclofenac dose-dependently induced gastric hemorrhages to a similar extent in both male and female mice. Gastric hemorrhage severity significantly correlated with gastric levels of myeloperoxidase, an objective measure of neutrophil infiltration. Similarly, JZL184 reduced gastric acidity, in controls as well as mice treated with pentagastrin, which stimulates gastric acid release. As hypothesized, JZL184 decreased gastric motility. Surprisingly, diclofenac also slowed gastric emptying, indicating that diclofenac-induced ulcers most likely occur through decreased gastric acid secretion, and not increased gastric motility, as measured in the present study. Thus, MAGL inhibition may proffer gastroprotection through modulating the secretory pathway of gastric hemorrhage. These data underscore the importance of sampling multiple time points and using both sexes in research, in addition to multiple mechanistic targets, and contribute to the basic understanding of NSAID-induced gastric inflammation.

CB1 positive allosteric modulation attenuates Δ9-THC withdrawal and NSAID-induced gastric inflammation

“…Furthermore, these gastroprotective effects can be blocked by the selective CB 1 antagonist rimonabant (Kinsey et al, 2011) or genetic deletion of CB 1 (Kinsey et al, 2011), suggesting endocannabinoid mediation occurs by CB 1 orthosteric binding. Accordingly, the monoacylglycerol lipase (MAGL) inhibitor JZL184 or KML29 block diclofenac-induced gastric hemorrhages by increasing 2-AG tone (Crowe and Kinsey, 2017;Ignatowska-Jankowska et al, 2014). The present studies expanded on these previous studies by testing the gastroprotective effects of CB 1 positive allosteric modulation per se, as well as in the presence of increased 2-AG tone, via a subthreshold dose of JZL184.…”

“…ZCZ011 was administered 75 min prior to testing in spontaneous withdrawal experiments, final THC injection in precipitated withdrawal experiments, or diclofenac gavage in ulcer experiments (Ignatowska-Jankowska et al, 2015). JZL184 was administered 120 min prior to diclofenac gavage (Crowe and Kinsey, 2017;Long et al, 2009). Doses were based on pilot data as well as published reports for ZCZ011 (Ignatowska-Jankowska et al, 2015) and JZL184 (Schlosburg et al, 2014).…”

“…The endogenous orthosteric ligands for CB 1 are anandamide and 2-arachidonoyl glycerol (2-AG), which are tightly regulated by synthetic and catabolic enzymes. Chemical inhibition of monoacylglycerol lipase (MAGL) increases tissue levels of 2-AG, resulting in reduced nociceptive pain, inflammation, gastric hemorrhage development, and somatic signs of cannabinoid withdrawal in mice (Crowe and Kinsey, 2017;Kinsey et al, 2009;Schlosburg et al, 2009). MAGL inhibitors present a few challenges, however, as at high doses they induce behavioral tolerance and CB 1 downregulation (Schlosburg et al, 2014(Schlosburg et al, , 2010.…”

Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

“…Obtained following the general procedure by the condensation between 1-(4-isobutylphenyl)cyclopropane-1-carboxylic acid (6)…”

“…The ability of FAAH inhibition to reduce the ulcerogenic potency of NSAIDs has also been seen with a peripherallyrestricted FAAH inhibitor, URB937 (N-cyclohexyl-carbamic acid, 3 0 -(aminocarbonyl)À6-hydroxy[1,1 0 -biphenyl] À 3-yl ester) and with indomethacin as NSAID 4 . A second endocannabinoid, 2-arachidonoylglycerol (2-AG) is primarily hydrolysed by monoacylglycerol lipase, and inhibition of that enzyme also reduces the ulcerogenic potency of diclofenac 5,6 .…”