Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis
Resat Cinar, … , Robert B. Innis, George Kunos
Resat Cinar, … , Robert B. Innis, George Kunos
Published July 21, 2016
Citation Information: JCI Insight. 2016;1(11):e87336. https://doi.org/10.1172/jci.insight.87336.
View: Text | PDF
Research Article Hepatology

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

  • Text
  • PDF
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.

Authors

Resat Cinar, Malliga R. Iyer, Ziyi Liu, Zongxian Cao, Tony Jourdan, Katalin Erdelyi, Grzegorz Godlewski, Gergő Szanda, Jie Liu, Joshua K. Park, Bani Mukhopadhyay, Avi Z. Rosenberg, Jeih-San Liow, Robin G. Lorenz, Pal Pacher, Robert B. Innis, George Kunos

×

Figure 5

Effects of rimonabant and MRI-1867 on gene expression of fibrosis markers.

Options: View larger image (or click on image) Download as PowerPoint
Effects of rimonabant and MRI-1867 on gene expression of fibrosis marker...
Wild-type, cnr1–/–, and nos2–/– mice received daily oral doses of 3 mg/kg/d of either compound for 2 weeks, starting on the day of bile duct ligation (BDL). Gene expression of collagen 1a (col1a), transforming growth factor-β1 (tgfβ1), α-smooth muscle actin (acta2), and tissue inhibitor of metalloproteinase-1 (timp1) was assayed by real-time PCR. Data represent mean ± SEM from 6 (nos2–/–) or 9 mice/group (wt, cnr1–/–). Data were analyzed by 1-way ANOVA followed by Dunnett’s multiple comparisons test. Significant difference from corresponding values in sham-operated controls (*P < 0.05) or from values in vehicle-treated BDL group (#P < 0.05).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts