الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Schistosomiasis is a chronic parasitic disease caused by trematode parasites of the genus Schistosoma. It is a major health problem responsible for significant morbidity and mortality worldwide. PPF is the most serious pathology associated with S. mansoni infection. The key pathogenic event is the activation of HSCs; the principal cell type responsible for ECMP formation. An important process in transcriptional regulation of HSCs is the modification of histones by histone modifying enzymes. One important class, HDACs, has been intensively studied as drug targets. Promising therapeutic effects of HDACIs have been emerged as potential anticancer, antifibrotic, and anti-parasitic agents. VPA, a class I HADCI, has been used for many years in chronic treatment of epilepsy. Different in vitro and in vivo studies have shown its prophylactic and therapeutic effect on fibrosis in different organs including experimental liver fibrosis. In the present study, a mouse model of schistosomiasis was used to test the ability of VPA to prevent liver fibrosis.
A pilot study was conducted to test the possible antischistosomal activity of VPA in S. mansoni infected mice. During this study 10 mice were infected with S. mansoni cercariae. Treatment with VPA 300mg/kg/day was from 5th to 7th WPI, and then estimation of the adult S. mansoni worm’s count was performed. No significant antischistosomal effect for VPA treatment was found.
Male Swiss albino mice were infected with S. mansoni cercariae. The mice were then divided into six groups each of 8:
(IA) uninfected, untreated (control),
(IB) S. mansoni-infected untreated,
(IC) Infected treated with PZQ,
(ID) Uninfected treated with VPA for 2 weeks,
(IE) Infected treated with VPA for 2 weeks,
(IF) Infected treated with PZQ and VPA for 2 weeks.
All VPA administrations were 300 mg/kg/day orally, dissolved in sterile distilled water at a concentration of 50 mg/ml and started on the 5th WPI for 2 weeks. All PZQ administrations were 500 mg/kg/day orally, suspended in 2% gum mucilage and was taken for 2 consecutive days on the 7th WPI.
Other corresponding groups (IIA, IIB, IID, IIE and IIF) were treated with the same schedule but with prolongation of VPA treatment to 5 weeks starting on the 5th WPI. On the 10th WPI, all mice were sacrificed. The blood was collected for separation of serum. Serum levels of ALT, AST, TGF-β1 and TNF-α were assayed. The livers were dissected and divided into two parts; one fixed in formalin for histolpathological examinations and the other one was freezed for determination of hydroxyproline content.
Infection of mice with S. mansoni resulted in a statistically significant elevation in serum levels of ALT and AST. Treatment of infected mice with PZQ alone, or its combination with VPA resulted in a statistically significant decrease in the liver transaminases tested. However, VPA treatment failed to cause a statistically significant decrease liver transaminase levels in infected mice. A significant difference was observed between treatment with PZQ and VPA combination and PZQ alone as regards ALT.
Infection with S. mansoni resulted in a statistically significant increase in serum levels of TGF-β1. Treatment of infected mice with PZQ, VPA, or with a combination of both drugs resulted in a statistically significant decrease in serum levels of TGF-β1 compared to infected group. Combining PZQ with VPA significantly augment its suppressing effect on TGF-β1.
Infection of mice with S. mansoni resulted in a significant increase in the serum levels of TNF-α. Treatment of infected mice with PZQ, VPA, or with a combination of both drugs resulted in a statistically significant decrease in serum levels of TNF-α compared to infected group. A statistically significant decrease in TNF-α was found with treatment of S. mansoni infected mice with VPA or its combination with PZQ compared with PZQ treatment alone.
Infection of mice with S. mansoni significantly increases liver hydroxyproline. Treatment of infected mice with PZQ, or VPA or the combination of the 2 drugs resulted in a statistically significant decrease in the liver hydroxyproline content compared to the infected group. Combining PZQ with VPA resulted in a statistically significant decrease in the liver hydroxyproline content compared to the use of PZQ alone.
No statistically significant difference was observed between S. mansoni infected mice received VPA for 2 weeks and for 5 weeks regarding the different studied parameters.
Histopathological examination of livers from mice infected with S. mansoni showed large fibrocellular granulomas in the hepatic parenchyma with a central zone of eggs surrounded by inflammatory cells and an outer zone of fibrous tissue. Treatment with PZQ decreased granuloma sizes with degeneration of eggs. Livers of infected mice treated with VPA revealed regression of the granulomatous inflammatory reaction and marked improved of hepatic lobules architecture. The granulomas were few, small, abortive and ill-formed. Livers of infected mice that received PZQ