Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis

Abstract

BackgroundPraziquantel (PZQ) is an isoquinoline derivative (2-cyclohexylcarbonyl-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino{2,1-a}-isoquinoline-4-one), and is currently the drug of choice for all forms of schistosomiasis. Silymarin, a standardized milk thistle extract, of which silibinin is the main component, is known for its hepatoprotective, anti-inflammatory, antioxidant activities, and hepatocyte regeneration. This study investigates the anti-inflammatory/anti-fibrotic effects of silymarin and/or PZQ on schistosomal hepatic fibrosis.MethodsSchistosoma mansoni-infected mice were divided into two large groups (I & II), each with four subgroups and were run in parallel. (i) Infected untreated; (ii) treated with silymarin, starting from the 4th (3 weeks before PZQ therapy) or 12th (5 weeks after PZQ therapy) weeks post infection (PI); (iii) treated with PZQ in the 7th week PI; and (iv) treated with silymarin, as group (ii) plus PZQ as group (iii). Comparable groups of uninfected mice run in parallel with the infected groups. Mice of groups I and II were killed 10 and 18 weeks PI, respectively. Hepatic content of hydroxyproline (HYP), serum levels and tissue expression of matrix metalloproteinase-2 (MMP-2), transforming growth factor-β1 (TGF-β1) and number of mast cells were determined. In addition, parasitological, biochemical and histological parameters that reflect disease severity and morbidity were examined.ResultsSilymarin caused a partial decrease in worm burden; hepatic tissue egg load, with an increase in percentage of dead eggs; modulation of granuloma size, with significant reduction of hepatic HYP content; tissue expression of MMP-2, TGF-β1; number of mast cells, with conservation of hepatic reduced glutathione (GSH). PZQ produced complete eradication of worms, eggs and alleviated liver inflammation and fibrosis. The best results were obtained, in most parameters studied, in groups of mice treated with silymarin in addition to PZQ.ConclusionsOur results point to silymarin as a promising anti-inflammatory and anti-fibrotic agent; it could be introduced as a therapeutic tool with PZQ in the treatment of schistosomal liver fibrosis, but further studies on mechanisms of silymarin and PZQ in chronic liver diseases may shed light on developing therapeutic methods in clinical practice.

Cytokine patterns in experimental schistosomiasis mansoni infected mice treated with silymarin

“…These results agreed with the previous studies (Mata-Santos et al 2010;Rabia et al 2010;El-Lakkany et al 2012). Using Silymarin as an antifibrotics drug can inhibit hepatic stellate cells activation that subsequently reduced the production of extracellular matrix components and slow down the progression of liver fibrosis (Afdhal and Nunes 2004;Wu et al 2009).…”

“…Silymarin, a standardized milk thistle extract, of which silibinin is the main component, is known for its hepatoprotective and promotes protein synthesis that helps in hepatocyte regeneration (El-Lakkany et al 2012). This effect could be attributed to its role as an antioxidant, antifibrotic, and antiinflammatory/immunomodulatory agent (Mata-Santos et al 2010).…”

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

“…Recently, silymarin was demonstrated to be capable of reducing transforming growth factor ␤1 (TGF-␤1) at the acute phase and the number of mast cells in mice infected with S. mansoni (42). The authors associated the silymarin-induced reduction of fibrosis with a reduction in the levels of TGF-␤1 in serum.…”

“…It has been previously demonstrated that other antioxidants also have the ability to prevent schistosomiasis-induced fibrosis when adminis- tered in the acute phase (4,5). El-Lakkany and coworkers (2012), treating infected mice with silymarin from 84 to 126 dpi, observed a slight decrease in the parasite burden and then in fibrosis, but the effect was smaller than that of praziquantel alone and possibly secondary to the decrease in burden (42). Herein, we did not observe alterations in the deposition of eggs in liver and intestinal tissues, which could suggest that there is no difference in parasite burden.…”

Effect of silybum marianum in treatment and prevention of hepatotoxicity in patients undergoing reinduction therapy for acute lymphoblastic leukemia (ALL)

“…Side effects included nausea and vomiting, neuropathy, diabetes and pancreatitis that all of them in the control group were higher and pancreatitis was not observed in the case group. It should be noted that about the side effects of Silymarin, particularly its longterm side effects, some studies have been conducted but further studies are recommended about it [11][12][13][14]. Hosseini et al in a study showed that treatment with Silymarin in patients with type II diabetes have had significant effects on gylcemic parameters improvement of the patients which also in the present study the FBS values in Silymarin group were significantly decreased compared to the control group.…”