Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis
Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis
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DOI：
10.1172/jci.insight.87336
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发表时间：
2016-07-21
期刊：
影响因子：
8
通讯作者：
Kunos, George
中科院分区：
文献类型：
--
作者：
Cinar, Resat;Iyer, Malliga R.;Kunos, George
肝纤维化是慢性肝损伤的结果，是肝硬化和肝细胞癌的中转站，缺乏有效的治疗。内源性大麻素通过大麻素-1受体（CB 1 R）起作用，诱导促纤维化基因表达并促进易患肝纤维化的病理。CB 1 R拮抗剂产生相反的作用，但由于神经精神副作用，其治疗发展停止。诱导型一氧化氮合酶（iNOS）也促进肝纤维化及其潜在的病理学，但迄今为止测试的iNOS抑制剂在炎症性疾病中显示出有限的治疗效果。在这里，我们介绍了一种外周限制，口服生物可利用的CB 1 R拮抗剂，它在肝脏中积累，释放iNOS抑制性离去基团。在由CCl 4或胆管结扎诱导的纤维化小鼠模型中，混合CB 1 R/iNOS拮抗剂超过CB 1 R拮抗剂利莫那班或iNOS抑制剂1400 W的抗纤维化功效，而不诱导CNS中的焦虑样行为或CB 1 R占用。该混合抑制剂还靶向CB 1 R非依赖性、iNOS介导的促纤维化途径，包括增加的PDGF、Nlrp 3/Asc 3和整合素α v β 6信号传导，这是通过其在cnr 1（-/-）小鼠中抑制这些途径的能力而判断的，但在nos 2（-/-）小鼠中不具有这种能力。此外，它能够减缓纤维化进展并减弱已建立的纤维化。因此，双靶点外周CB 1 R/iNOS拮抗剂在肝纤维化中具有治疗潜力。
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.