Hernández-Vázquez Eduardo, Ocampo-Montalban Hugo, Cerón-Romero Litzia, Cruz Miguel, Gómez-Zamudio Jaime, Hiriart-Valencia Guadalupe, Villalobos-Molina Rafael, Flores-Flores Angelica, Estrada-Soto Samuel
Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad de México 04510, México.
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, México.
Eur J Pharmacol. 2017 May 15;803:159-166. doi: 10.1016/j.ejphar.2017.03.036. Epub 2017 Mar 18.
Diabetes is a major health problem and a predisposition factor for further degenerative complications and, therefore, novel therapies are urgently needed. Currently, cannabinoid receptor 1 (CB receptor) antagonists have been considered as promissory entities for metabolic disorders treatment. Accordingly, the purpose of this work was the evaluation of the sub-acute antidiabetic, anti-hyperglycemic, antidyslipidemic and toxicological profile of ENV-2, a potent hypoglycemic and antioxidant CB receptor antagonist. In this study, ENV-2 showed a pronounced anti-hyperglycemic effect even at a dose of 5mg/kg (P<0.05) in a glucose tolerance test on normoglycemic rats. Moreover, after administration of ENV-2 (16mg/kg) to diabetic rats, a prominent antidiabetic activity was observed (P<0.05), which was higher than glibenclamide. Sub-acute treatment (10 days) of ENV-2 resulted in a significant reduction of plasma glucose (P<0.05). Also, the levels of peripheral lipids were improved; blood triacylglycerols (TG) and cholesterol (CHOL) were diminished (P<0.05). In addition, it was found that ENV-2 reduced IL-1β and IL-18 mRNA expression in adipose tissue (P<0.05). Due to the satisfactory outcomes, we were interested in evaluating the toxicity of ENV-2 in both acute and sub-chronic approaches. Regarding the acute administration, the compound resulted to be non-toxic and was grouped in category 5 according to OECD. It was also found that sub-chronic administration did not increase the size of the studied organs, while no structural damage was observed in heart, lung, liver and kidney tissues. Finally, neither AST nor ALT damage hepatic markers were augmented.
糖尿病是一个主要的健康问题，也是进一步发生退行性并发症的一个易感因素，因此，迫切需要新的治疗方法。目前，大麻素受体1（CB受体）拮抗剂已被视为治疗代谢紊乱的有前景的药物。因此，本研究的目的是评估强效降糖和抗氧化CB受体拮抗剂ENV-2的亚急性抗糖尿病、降血糖、抗血脂异常和毒理学特征。在本研究中，在正常血糖大鼠的葡萄糖耐量试验中，ENV-2即使在5mg/kg的剂量下也显示出显著的降血糖作用（P<0.05）。此外，给糖尿病大鼠施用ENV-2（16mg/kg）后，观察到显著的抗糖尿病活性（P<0.05），高于格列本脲。ENV-2的亚急性治疗（10天）导致血浆葡萄糖显著降低（P<0.05）。此外，外周血脂水平得到改善；血液中的三酰甘油（TG）和胆固醇（CHOL）降低（P<0.05）。此外，发现ENV-2降低了脂肪组织中IL-1β和IL-18 mRNA的表达（P<0.05）。由于结果令人满意，我们有兴趣评估ENV-2在急性和亚慢性给药方式下的毒性。关于急性给药，该化合物无毒，根据经合组织的标准被归类为5类。还发现亚慢性给药并未增加所研究器官的大小，同时在心脏、肺、肝脏和肾脏组织中未观察到结构损伤。最后，AST和ALT这两种肝损伤标志物均未升高。
