Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

Abstract

Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases. Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group. In mouse models of fibrosis induced by CCl4 or bile duct ligation, the hybrid CB1R/iNOS antagonist surpassed the antifibrotic efficacy of the CB1R antagonist rimonabant or the iNOS inhibitor 1400W, without inducing anxiety-like behaviors or CB1R occupancy in the CNS. The hybrid inhibitor also targeted CB1R-independent, iNOS-mediated profibrotic pathways, including increased PDGF, Nlrp3/Asc3, and integrin αvβ6 signaling, as judged by its ability to inhibit these pathways in cnr1−/− but not in nos2−/− mice. Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

“…Endocannabinoid levels are increased locally in certain organs and/or in the systemic circulation in disorders such as obesity, diabetes, and liver fibrosis (21,(28)(29)(30). Eventually, this results in an overactive endocannabinoid/CB 1 R system that contributes to disease pathology.…”

“…We developed MRI-1867 as a dual-target peripheral CB 1 R/iNOS inhibitor and demonstrated its superior efficacy in rodent models of liver fibrosis relative to inhibition of CB 1 R or iNOS alone (21). MRI-1867 and rimonabant are equipotent in antagonizing CB 1 R. We selected an oral dose of 10 mg/kg for rimonabant and MRI-1867 and an intraperitoneal dose of 10 mg/kg for AM6545, because this dose …”

“…Endocannabinoids are bioactive lipids that act on cannabinoid receptors, CB 1 R and CB 2 R, that also recognize and mediate the effects of marijuana (16). Endocannabinoids acting via CB 1 R promote fibrosis progression in multiple organs, including liver (17)(18)(19)(20)(21), kidney (22,23), heart (24), and skin (25), and CB 1 R has been linked to radiation-induced PF in mice (26). In addition to promoting fibrosis, activation of CB 1 R is proinflammatory in chronic inflammatory diseases (27,28), whereas the brain-penetrant CB 1 R antagonist/inverse agonist rimonabant mitigates liver fibrosis in animal models (17).…”

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

“…This type of approach would benefit from the use of lower doses of the drugs, thus limiting possible side effects, while acting on different biological systems that participate in the regulation of energy balance, possibly leading to greater therapeutic success. For instance, a recent study by Kunos et al has characterized the effects of a hybrid inhibitor of peripheral CB 1 R and inducible nitric oxide synthase (iNOS) for the treatment of liver fibrosis (123,124). This orally bioavailable compound accumulates in the liver where it releases an iNOS inhibitor, providing the possible advantage of an organ-targeted action.…”

“…This orally bioavailable compound accumulates in the liver where it releases an iNOS inhibitor, providing the possible advantage of an organ-targeted action. When administered to mice, the hybrid inhibitor was able to slow fibrosis progression and to attenuate established fibrosis (123).…”