Effect of silibinin on endothelial dysfunction and ADMA levels in obese diabetic mice

Abstract

BackgroundCardiovascular diseases (CVD) in diabetic patients have endothelial dysfunction as a key pathogenetic event. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), plays a pivotal role in endothelial dysfunction. Different natural polyphenols have been shown to preserve endothelial function and prevent CVD. In this study, we assessed the effect of silibinin, a widely used flavonolignan from milk thistle, on ADMA levels and endothelial dysfunction in db/db mice.MethodsEight-week-old db/db mice were administrated a 20 mg/Kg i.p. daily dose of silibinin (n = 6) or vehicle (n = 6) for four weeks. Heterozygous lean db/m mice served as control. Plasma, aorta and liver ADMA levels were determined by ELISA. Vascular reactivity to phenilephrine (PE), acetylcholine (ACh), sodium nitroprusside (SNP) and ADMA was assessed in isolated aortic segments, in wire myograph.ResultsPlasma and aorta ADMA levels were higher in db/db than in control lean mice. Silibinin administration markedly decreased plasma ADMA; consistently, aorta ADMA was reduced in silibinin-treated animals. Plasma and aorta ADMA levels exhibited a positive correlation, whereas liver ADMA was inversely correlated with both plasma and aorta ADMA concentrations. Endothelium-(NO)-dependent vasodilatation to ACh was impaired in db/db mice and was restored in the silibinin group, in accordance with the observed reduction of plasma and vascular levels of ADMA. Endothelium-independent vasodilatation to SNP was not modified by silibinin administration; contractile tone induced in isolated aorta from db/db mice by challenging with exogenous ADMA was not affected by the treatment.ConclusionsSilibinin markedly improves endothelial dysfunction in db/db mice by reducing circulating and vascular ADMA levels. Clinical studies are warranted to assess the efficacy of silibinin for cardiovascular protection.

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

“…Indeed, liver JNK phosphorylation was reduced to control levels in treated animals [57]. In obese diabetic mice, silybin administration markedly decreased plasma levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase that, as known, plays a pivotal role in endothelial dysfunction [58]. Finally, the antiviral action of silybin against HCV replication is also related to its antioxidant properties.…”

The Therapeutic Potential of Milk Thistle in Diabetes

“…Silibin decreases ADMA levels in db/db mice to a level that is lower than in their heterozygous lean counterparts (db/m), which served as controls [17]. In experimentally induced diabetic retinopathy, silibin seems to have a favorable effect as vascular leukostasis and levels of retinal ICAM-1 are significantly reduced [18].…”

Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis

“…Potent scavenging properties have been demonstrated in hepatic and non-hepatic cells; 11,12 several in vivo studies showed that silibinin may exert beneficial effects in different types of liver injury 13,14 and in diabetes and its complications. 15 Previous clinical findings evidenced the efficacy of silibinin on insulin resistance and liver injury, assessed by surrogate markers, in patients with NASH; 16 the improvement of liver histology after silibinin treatment was recently reported in a multicenter randomized controlled trial. 17 However, the molecular mechanisms associated with the hepatoprotective activity of silibinin in NASH remain to be elucidated.…”