NIAAA Spectrum: Dual-Targeting Strategy Shows Promise Against Liver Fibrosis
Liver fibrosis is a consequence of chronic liver injury associated with alcoholic or nonalcoholic fatty liver disease, viral hepatitis, or metabolic diseases, and can lead to cirrhosis and even cancer. While there are no effective treatments for liver fibrosis, previous research has shown that compounds that block receptors for molecules similar to those found in the marijuana plant (endocannabinoids) can interfere with the development of liver fibrosis. However, the development of therapies based on these cannabinoid-1 receptor (CB1R)-blocking compounds was halted, because they have unwanted neuropsychiatric side effects of CB1R-blocking agents acting in the brain.
In a new study, NIAAA-supported researchers have developed a CB1R-blocking compound that could avoid those side effects, because it accumulates in the liver without penetrating the brain. An added benefit of the new compound is that it also targets an enzyme called inducible nitric oxide synthase (iNOS), which also promotes the development of liver fibrosis. In studies that used mouse models of liver fibrosis, the researchers found that the new compound surpassed the antifibrotic ability of other CB1R blockers or iNOS inhibitors without inducing anxiety-like behaviors or CB1R blockade in the central nervous system.
The researchers note that the dual targeting of peripheral CB1R and iNOS exemplifies the therapeutic advantage of simultaneously hitting more than one molecule involved in a pathogenic process, particularly in light of emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases. They therefore conclude that the approach illustrated by their study shows promise as an effective anti-fibrotic strategy.
Cinar, R.; Iyer, M.R.; Liu, Z.; Cao, Z.; Jourdan, T.; Erdelyi, K.; Godlewski, G.; Szanda, G.; Liu, J.; Park, J.K.; Mukhopadhyay, B.; Rosenberg, A.Z.; Liow, J.S.; Lorenz, R.G.; Pacher, P.; Innis, R.B.; and Kunos, G. Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis. JCI Insight 1(11):e87336, 2016. PMID: 27525312