“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.

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.

Regarding the pharmacodynamics of the hybrid CB₁R/iNOS inhibitor, two important principles have emerged from efforts to develop effective antifibrotic therapies. First, antifibrotic treatment strategies could aim to control the primary disease, to inhibit fibrogenic gene expression and signaling, to promote molecular mechanisms involved in fibrosis regression, or a combination of these. Second, with multiple molecular mechanisms and signaling pathways involved in fibrosis, targeting more than one could increase antifibrotic efficacy, and the hybrid CB₁R/iNOS inhibitor embodies optimal characteristics on both accounts.

As to the first principle, both the endocannabinoid/CB₁R system and iNOS are ideal targets, as they are known to be involved directly in the fibrotic process and also in the conditions predisposing to liver fibrosis, as detailed in the Introduction. An emerging major predisposing factor to liver fibrosis is nonalcoholic fatty liver disease, and CB₁R blockade has proven effective in mitigating obesity-related hepatic steatosis in both rodent models and humans. The other two major predisposing factors, alcoholic fatty liver disease and viral hepatitis, also involve increased CB₁R activity. Hepatic CB₁R expression is induced either by chronic ethanol intake or the hepatitis C virus, and CB₁R blockade mitigates alcohol-induced steatosis and inhibits hepatitis C virus production.

The dual targeting of peripheral CB₁R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases.

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

http://insight.jci.org/articles/view/87336