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The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation.

ABSTRACT: 2-arachidonoylglycerol (2-AG) is an endocannabinoid whose hydrolysis is predominantly catalysed by the enzyme monoacylglycerol lipase (MAGL). The development of MAGL inhibitors could offer an opportunity to investigate the anti-inflammatory and anti-nociceptive role of 2-AG, which have not yet been elucidated. On these bases, URB602, a MAGL inhibitor, was tested in a murine model of inflammation/inflammatory pain.Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice. The highest dose to be employed has been selected performing the tetrad assays for cannabimimetic activity in mice. URB602 anti-inflammatory and anti-nociceptive efficacy (assessed by plethysmometer and plantar test, respectively) was evaluated both in a preventive regimen (drug administered 30 min before carrageenan) and in a therapeutic regimen (URB602 administered 30 min after carrageenan). To elucidate the cannabinoid receptor involvement, rimonabant and SR144528, CB1 and CB2 selective antagonists, respectively, were given 15 min before URB602.Systemic administration of URB602 elicited a dose-dependent anti-oedemigen and anti-nociceptive effect that was reversed exclusively by the CB2 receptor antagonist. The efficacy of URB602 persisted also when the compound was administered in a therapeutic regimen, suggesting the ability of URB602 to improve established disease.The present report highlighted the ability of the selective MAGL inhibitor, URB602, to prevent and treat an acute inflammatory disease without producing adverse psychoactive effects. The data presented herein also contributed to clarify the physiological role of 2-AG in respect to inflammatory reactions, suggesting its protective role in the body.

SUBMITTER: Comelli F

PROVIDER: S-EPMC2190015 | biostudies-other | 2007 Nov

REPOSITORIES: biostudies-other

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Project description:Background: Patients with rheumatoid arthritis (RA) experience joint swelling and cartilage destruction resulting in chronic pain, functional disability, and compromised joint function. Current RA treatments, including glucocorticoid receptor agonists, produce adverse side effects and lack prolonged treatment efficacy. Cannabinoids (i.e., cannabis-like signaling molecules) exert anti-inflammatory and analgesic effects with limited side effects compared to traditional immunosuppressants, making them excellent targets for the development of new arthritic therapeutics. Monoacylglycerol lipase (MAGL) inhibition reduces inflammation in mouse models of acute inflammation, through cannabinoid receptor dependent and independent pathways. The current study investigated the efficacy of inhibiting synthetic and catabolic enzymes that regulate the endocannabinoid 2-arachidonoylglycerol (2-AG) in blocking paw inflammation, pain-related behaviors, and functional loss caused by collagen-induced arthritis (CIA). Methods: Male DB1A mice subjected to CIA were administered the glucocorticoid agonist dexamethasone (DEX), MAGL inhibitor JZL184 (8 or 40 mg/kg, s.c.), alone or in combination, or diacylglycerol lipase β (DAGLβ) inhibitor KT109 (40 mg/kg, s.c.). CIA-induced deficits were assayed by arthritic clinical scoring, paw thickness measurements, and behavioral tests of pain and paw function. Results: DEX or dual administration with JZL184 reduced paw thickness and clinical scores, and JZL184 dose-dependently attenuated grip strength and balance beam deficits caused by CIA. Traditional measures of pain-induced behaviors (hyperalgesia and allodynia) were inconsistent. The antiarthritic effects of JZL184 (40 mg/kg) were largely blocked by coadministration of the CB2 antagonist SR144528, and the DAGLβ inhibitor KT109 had no effect on CIA, indicating that these effects likely occurred through CB2 activation. Conclusions: MAGL inhibition reduced paw inflammation and pain-depressed behavioral signs of arthritis, likely through an endocannabinoid mechanism requiring CB2. These data support the development of MAGL as a target for therapeutic treatment of inflammatory arthritis.

Project description:Endocannabinoid 2-arachidonoylglycerol (2-AG) is an anti-nociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by monoacylglycerol lipase (MAGL). In this study, we investigated the effects of MAGL inhibition on intestinal permeability and explored the possible mechanism. A rat model of severe acute pancreatitis (SAP) was established. Rats were divided into three groups according to treatment. We analyzed intestinal permeability to fluorescein isothiocyanate-dextran and the levels of inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and 2-AG. Hematoxylin and eosin staining was used to assess histological tissue changes. In vivo intestinal permeability was evaluated by transmission electron microscopy. We obtained ileum tissues, extracted total RNA, and applied RNA-sequencing. Sequencing data were analyzed by bioinformatics. Inflammatory factor levels were higher, while 2-AG levels were lower in the SAP group compared with the control group. Administration of JZL184 to rats with SAP increased the levels of 2-AG and lowered the levels of IL-6 and TNF-α. Notably, intestinal permeability was improved by JZL184 as demonstrated by fluorescein isothiocyanate-dextran measurement, hematoxylin and eosin staining, and transmission electron microscopy. RNA-sequencing showed significant transcriptional differences in SAP and JZL184 groups compared with the control group. KEGG analysis showed that the up- or downregulated genes in multiple comparison groups were enriched in two pathways, focal adhesion and PI3K-Akt signaling pathways. Differential alternative splicing (AS) genes, such as Myo9b, Lsp1, and Git2, have major functions in intestinal diseases. A total of 132 RNA-binding proteins (RBPs) were screened by crossing the identified abnormally expressed genes with the reported RBP genes. Among them, Hnrnpdl coexpressed the most AS events as the main RBP. MAGL inhibition improved intestinal mucosal barrier injury in SAP rats and induced a large number of differentially expressed genes and alternative splicing events. Hnrnpdl might play an important role in improving intestinal mucosal barrier injury by affecting alternative splicing events.

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The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation.

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