In vivo antioxidant and antigenotoxic evaluation of an enaminone derivative BDHQ combined with praziquantel in uninfected and Schistosoma mansoni infected mice (original) (raw)
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Experimental Parasitology, 2008
Schistosoma mansoni (S. mansoni) eggs trapped in the host liver elicit a chain of oxidative processes that may be, at least in part, responsible for the pathology and progression of fibrosis associated with schistosomal hepatitis. This study was designed to assess the protective effect of the antioxidant coenzyme-Q10 (Co-Q10) against experimental S. mansoni-induced oxidative stress in the liver, and its potential role as an adjuvant to praziquantel (PZQ) therapy. The oxidative stress and overall liver function were improved under Co-Q10 therapy as evidenced by significant reduction in oxidative stress markers and preservation of antioxidant factors. Liver fibrosis was also reduced with a positive impact on liver function. Moreover, addition of Co-Q10 to PZQ therapy caused: significant reduction of liver egg load, significant improvement of the redox status, and lastly decreased liver fibrosis.
The Korean Journal of Parasitology, 2013
The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P < 0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P < 0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.
Pharmacological Research, 1990
Cytophotometric measurement of the effect of praziquantel (500 mg/kg for 2 days) versus hycanthone (60 mg/kg for 3 days) on hepatocyte nuclear deoxyribonucleic acid (DNA) content was evaluated in Schistosoma mansoni infected mice. Drugs were given 8 weeks post-infection and repeated weekly for 4 weeks. DNA values of infected untreated control and infected drug treated groups were related to the median and upper diploid DNA values of normal control. Schistosoma mansoni infection per se did not change the hepatocyte DNA content, yet aneuploidy was 16. 7%. Praziquantel did not result in significant change of DNA content or ploidy, while hycanthone resulted in marked significant increase of DNA content (328. 9%) and aneuploidy (100%), compared to infected untreated control. Histopathological examination revealed hyperchromatic nuclei with mitosis in the hepatocytes of hycanthone treated mice, but not in praziquantel treated animals. These DNA changes were found to correlate with the reported safety of praziquantel and the carcinogenicity of hycanthone. KEY wokos: hepatocyte DNA, schistosomicidal drugs.
The Journal of Basic & Applied Zoology, 2014
The present study was designed to assess the relationship between anti-schistosomal effect of the antimalarial drug mefloquine (Mef) and the oxidative stress status of Schistosoma mansoni infected mice. Forty mice were divided into eight groups (5 mice/group); control (I, II), infected (III, IV), Mef low dosage (200 mg/kg) (V, VI), and Mef high dosage (400 mg/kg) (VII, VIII). Mef (200 and 400 mg/kg) was administered orally as a single dose at days 14 and 35 post infection (PI). All mice were sacrificed after 8 weeks PI. Oral administration of Mef (200 or 400 mg/kg) at day 14 or 35 PI reduced the total worm burden by 84%, 78% and 94%, 85.7% respectively. Meanwhile, Mef treatment reduced egg load in the intestine and the liver. Following Mef (200 and 400 mg/kg) treatment to mice at day 14 or 35 PI, the oogram pattern showed complete disappearance of all immature and mature ova. Treatment of mice with Mef at the two tested doses significantly decreased the activities of ALT, AST, ALP and GGT enzymes as compared to infected untreated group. However, administration of Mef (200 and 400 mg/kg) at day 14 or 35 PI significantly (P < 0.05) decreased the MDA level and increased the levels of GSH and CAT as compared to infected untreated group. In conclusion, Mef is an effective curative anti-schistosomal and anti-oxidative drug as it alleviates the biochemical and the oxidative stress alterations. Also, Mef has schistosomicidal and ovicidal effects.
The Egyptian Journal of Hospital Medicine, 2009
Background: This study deals with the evaluation of parasitological, histopathological and biochemical effect of Praziquantel (PZQ) and Mirazid (MZ) with or without Selenium-ACE (Se-ACE) on male albino mice infected with S.mansoni and trying to evaluate the antioxidant effect of Se-ACE and its role in reducing the severity of the infection. Results: The obtained results indicated that treatment with PZQ produced more reduction in worm burden and ova count/gm liver than MZ compared to the infected control group. PZQ showed the highest reduction in liver granuloma number and diameter when compared to MZ group while both drugs showed a significant effect in restoration of the liver transaminases and protein fractions towards their normal levels indicating the safety of both drugs as anti S. mansoni chemotherapeutics, Se-ACE showed a high efficacy as a co-treatment, potentiating the effect of PZQ and MZ in reducing the worm burden, ova count/gm liver, number and diameter of liver granuloma and restoration of liver transaminases and protein fractions to their normal levels during treatment of S. mansoni infection. Conclusion: the rank order of potency in protection against liver cell damage was PZQ 500 mg/kg > MZ 600 mg/kg where Se-ACE showed a couraging criterion as a co-treatment potentiating the effect of the antischistosomal medications through its anti-oxidant activity.
Parasitology Research, 2012
Schistosomiasis is an endemic disease in 74 countries causing more than 250,000 deaths every year. Accordingly, the development of an effective drug for eradication of schistosomiasis is an open research field. The current chemotherapy for control is praziquantel (PZQ). However, PZQ does not improve liver fibrosis. Therefore, the aim of this study is to evaluate the combined effect of alpha lipoic acid (ALA) with PZQ on the liver fibrosis induced by Schistosoma mansoni challenged mice. Evaluation was based on the worm burden count, ova load, granuloma size, and histopathology of the liver. Reduced glutathione (GSH) was measured in the tissue as a biomarker for impaired antioxidant function. Malondialdehyde (MDA) was also measured in the tissue as a biomarker for oxidative stress. The serum level of matrix metalloproteinase 1 was measured as a biomarker for fibrotic status of the liver. Liver function enzymes such as ALT, AST, and GGT were also measured. Four groups of ten mice each were used in this study. The first group was infected with 50±10 S. mansoni cercariae. The second group was also infected and was treated with PZQ 9 weeks post-infection (PI). The third group was treated with PZQ and ALA 9 weeks PI. The fourth group was used a healthy control. The present study revealed remarkable improvement in all parameters measured (parasitological and biochemical) as well as significant improvement of hepatic pathology in the third group which was treated with PZQ and ALA. The treatment of mice with PZQ and ALA results in reduction in the worm burden, egg count, and granuloma size. Furthermore, this combined treatment increased the tissue level of the antioxidant (GSH) and decreased the tissue level of MDA in this group.
Parasites & Vectors
Background: Praziquantel (PZQ) is the mainstay of schistosomiasis control and has been successfully used for decades. However, its mechanism of action is not fully understood. While the majority of studies have been conducted on Schistosoma mansoni, it is not known which enantiomer, R-or S-praziquantel (R-/S-PZQ), is responsible for the activity on Schistosoma haematobium. Methods: In vitro and in vivo studies were conducted to evaluate the activity of R-and S-PZQ, racemic PZQ and the main human metabolite, namely trans-4-OH-PZQ, on S. haematobium. IC 50 values on adult S. haematobium were determined in vitro. Dose-response relationship studies were performed in golden Syrian hamsters, harbouring a chronic S. haematobium infection. Results: R-PZQ displayed the highest activity against adult worms in vitro, revealing an IC 50 of 0.007 μg/ml at 4 h and 0.01 μg/ml at 72 h. In contrast, S-PZQ was 501× less active (eudysmic ratio at 4 h), with an IC 50 of 3.51 and 3.40 μg/ml (4 and 72 h, respectively). Racemic PZQ and trans-4-OH-PZQ resulted in an IC 50 of 0.03 μg/ml and 1.47 μg/ml both at 4 and 72 h, respectively. In vivo, R-PZQ was the most potent drug with worm burden reductions (WBRs) of 98.5, 75.6 and 73.3% at 125.0, 62.5 and 31.0 mg/kg, respectively. A single oral dose of 250.0 mg/kg PZQ resulted in a WBR of 99.3%. S-PZQ was highly active in vivo at 250.0 and 500.0 mg/kg with WBRs of 83.0 and 94.1%, respectively. The lowest tested dose of S-PZQ, 125.0 mg/kg, showed moderate activity (WBR of 46.7%). The calculated ED 50 for R-and S-PZQ were 24.7 and 127.6 mg/kg, respectively, with a corresponding eudysmic ratio of 5.17. Conclusion: Our data support the theory of R-PZQ driving the antischistosomal activity. Interestingly, also S-PZQ proved to possess a significant activity towards S. haematobium, particularly in vivo.
2012
Schistosomiasis is one of the world's greatly neglected tropical diseases, and its control is largely dependent on a single drug, praziquantel (PZQ). Here, two novel 8-hydroxyqinoline-5-sulfonamido derivatives, compounds 3 and 4, mansoni adult worms to 200 μg/mL concentrations of either compound 3 or 4 reduced the motor activity and caused their death within 24 hour (h). However, adult worms incubated in a medium containing 50 μg/mL of either compound 3 or 4 showed decrease motor activity and dead after 120 and 144 h of incubation, respectively. Different concentrations of both compounds induced partial tegumental alterations in 40-50% of tested worms. Additionally, 50 μg/mL concentration of compound 3 caused 58% and 75% reduction in egg production; however compound 4 caused 51% and 60% reduction in oviposition after 48 and 72 h of incubation, respectively. Furthermore molecular docking of both new compounds was carried out using Molsoft ICM pro 3.5-0a to investigate the binding affinity and binding mode to thioredoxin glutathione reductase enzyme (TGR), a potential drug target for anti-schistosomal activity. The docking results revealed moderate to high affinity of both compounds towards TGR. It is suggested that the in vitro schistosomicidal effects of our novel 8dicate the potential schistosomicidal effects of both 8-hydroxyqinoline derivatives.
Biomedical and environmental sciences : BES, 2013
To investigate the possible effect of artesunate (ART) on schistosome thioredoxin glutathione reductase (TGR) and cytochrome c peroxidase (CcP) in Schistosoma mansoni-infected mice. A total of 200 laboratory bred male Swiss albino mice were divided into 4 groups (50 mice in each group). Group I: infected untreated group (Control group) received a vehicle of 1% sodium carbonyl methylcellulose (CMC-Na); Group II: infected then treated with artesunate; Group III: infected then treated with praziquantel, and group IV: infected then treated with artesunate then praziquantel. Adult S. mansoni worms were collected by Animal Perfusion Method, tissue egg counted, TGR, and CcP mRNA Expression were estimated of in S. mansoni adult worms by semi-quantitative rt-PCR. Semi-quantitative rt-PCR values revealed that treatment with artesunate caused significant decrease in expression of schistosome TGR and CcP in comparison to the untreated group. In contrast, the treatment with praziquantel did not ...