title: 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 CCl4or 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.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Malliga R
authors.initials: MR
authors.lastname: Iyer
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Laboratory of Oxidative Stress and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, Washington, DC, USA.
authors.forename: Zongxian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Tony
authors.initials: T
authors.lastname: Jourdan
authors.affiliation: Laboratory of Oxidative Stress and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, Washington, DC, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdelyi
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Gergő
authors.initials: G
authors.lastname: Szanda
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Park
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.affiliation: Kidney Diseases Section, National Institute on Diabetes, Digestive, and Kidney Diseases, Washington, DC, USA.|Children's National Medical Center, Washington, DC, USA.
authors.forename: Avi Z
authors.initials: AZ
authors.lastname: Rosenberg
authors.affiliation: Molecular Imaging Branch, National Institute on Mental Health, NIH, Bethesda, Maryland, USA.
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Robin G
authors.initials: RG
authors.lastname: Lorenz
authors.affiliation: Laboratory of Oxidative Stress and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, Washington, DC, USA.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Molecular Imaging Branch, National Institute on Mental Health, NIH, Bethesda, Maryland, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.affiliation: Laboratory of Physiologic Studies and.
authors.forename: George
authors.initials: G
authors.lastname: Kunos