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

被引：64

作者：

Cinar, Resat ^{[1
]}

Iyer, Malliga R. ^{[1
]}

Liu, Ziyi ^{[1
]}

Cao, Zongxian ^{[2
]}

Jourdan, Tony ^{[1
]}

Erdelyi, Katalin ^{[2
]}

Godlewski, Grzegorz ^{[1
]}

Szanda, Gergo ^{[1
]}

Liu, Jie ^{[1
]}

Park, Joshua K. ^{[1
]}

Mukhopadhyay, Bani ^{[1
]}

Rosenberg, Avi Z. ^{[3
,4
]}

Liow, Jeih-San ^{[5
]}

Lorenz, Robin G. ^{[6
]}

Pacher, Pal ^{[2
]}

Innis, Robert B. ^{[5
]}

Kunos, George ^{[1
]}

机构：

[1] NIAAA, Lab Physiol Studies, Washington, DC USA

[2] NIAAA, Lab Oxidat Stress & Tissue Injury, Washington, DC USA

[3] NIDDK, Kidney Dis Sect, Washington, DC USA

[4] Childrens Natl Med Ctr, Washington, DC 20010 USA

[5] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA

[6] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA

来源：

JCI INSIGHT | 2016年 / 1卷 / 11期

关键词：

NLRP3 INFLAMMASOME ACTIVATION; HEPATIC CB1 RECEPTORS; NONALCOHOLIC STEATOHEPATITIS; INTEGRIN ALPHA-V-BETA-6; ENDOCANNABINOID SYSTEM; INSULIN-RESISTANCE; BILIARY FIBROSIS; MOUSE MODELS; PROGRESSION; OBESITY;

D O I：

10.1172/jci.insight.87336

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 alpha v beta 6 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.

引用

页数：19

共 70 条

[41] Deficiency of iNOS-derived NO accelerates lipid accumulation-independent liver fibrosis in non-alcoholic steatohepatitis mouse model [J].