Table 1.
Reports of antioxidant effects on developmental stages of schistosomes and infection in murine models.
| Compound | Aim/Study | Treatment | Findings/Outcomes | Ref. |
|---|---|---|---|---|
| M. armillaris | Antischistosomal and antioxidant activity of essential oil on normal and infected S. mansoni mice in comparison to PZQ. | Oil 150 mg/kg orally from second week p.i., twice week for 6 weeks; PZQ 600 mg/kg, orally for 2 consecutive days, 8 weeks p.i. | Administration of PZQ and M. armillaris ameliorate the levels of GSH and lipid peroxides (MDA); Restored the activities of SOD and catalase; M. armillaris enhance antioxidant defense system reducing disease complications. | [111] |
| Limonin | Antischistosomal activity in vitro and in vivo harboring juvenile and adult S. mansoni worms. | Oral administration in a single dose of 50 or 100 mg/kg on day 21 p.i.; Same dose given on 56 p.i. | Limonin is more effective against immature stages rather adult worms also induce tegument alterations; Reduction of worm burden: at day 21 p.i. 70.0% and 83.3%; and day 56 p.i. 41.09 and 60.27%. Significant reduction in the hepatic (34.90% and 47.16%) and intestinal (46.67% and 56.1%) tissue egg load associated the oogram pattern with elevated dead egg levels; Also, ameliorate hepatic pathology with reduction in size and numbers of granulomas. | [112] |
| Pholoro-glucinol derivatives | Evaluation in vitro schistosomicidal activity of aspidin (AS), flavaspidic acid (FAA), methylene-bis-aspidinol (MbA) and desaspidin (DA) against S. mansoni adult worms. | AP-25 to 100 μM FAA-50 and 100 μM MbA-100 μM DA-25 to 100 μM |
AP and FAA decrease motor activity with tegumental alterations while MBA and DA also decrease motor activity but without tegumental alterations. At highest concentrations viability of worms were similar to positive controls (PZQ); Egg production and the development of eggs produced were inhibited; Probably, in vitro activity is related to the inhibition of oxidative phosphorylation pathways. | [113] |
| Hesperidin | Evaluation of antischistosomal activity in vitro and in vivo and compared to PZQ. Effect on parasite antigens. Treatments were administered on 6th week p.i. | In vitro: 50, 100 and 200 μg/mL. In vivo: Hesp-600 mg/kg bw (6 injections, 2 injections per week for 3 consecutive week); PZQ (2 consecutive days with 500 mg/kg bw. |
In vitro: At highest concentration, all males and females were dead while lower concentration had moderate effect. No activity on oogram pattern was seen. In vivo: Reduction of numbers of males, females and possibly worm pairs and total worm burden counts (47.5%) but was not higher than PZQ; significantly reduced tissue egg load. Augmented the mouse IgG response against soluble worm antigen protein, soluble egg antigen and cercarial preparation of S. mansoni. |
[114] |
| α-Lipoic acid | Study combined effect of ALA with PZQ on liver fibrosis induced by S. mansoni infection in mice. | PZQ-500 mg/kg divided into 2 doses 9 weeks p.i.: PZQ (same described) + ALA (single dose 30 mg/kg) daily for two months. | Combine regimen results in reduction in the worm burden (ALA: 7.63 ± 1.49; PZQ: 6.13 ± 1.89; PZQ + ALA: 36.50 ± 10.80), egg count and granuloma size. Recovered the level serum of ALT, AST and GGT and increased the tissue level of GSH and decreased MDA (biomarkers of antioxidant function and stress oxidative, respectively). | [115] |
| Resveratrol | Investigate effect of Resv on oxidative stress imposed on liver, lung, kidney, brain and spleen of S. mansoni-infected mice. | 20 mg/kg once daily for 2 weeks | Improvement of lipid metabolism and antioxidant profile by Resv which were not only restricted to liver but also other vital organs. Specific biomarkers of lung and brain homeostasis also showed remarkable improvement. | [116] |
| B. trimera | Assessment of antischistosomal activity agaisnt S. mansoni adult worms in vitro. | 4 concentrations of 24, 48, 91 and 130 µg/mL. | Antischistosomal activity at highest concentrations with significant reductions in motility; Total inhibition in egg laying when parasites were exposure to sub-lethal concentrations and separations of all couples. Morphological changes on the tegument of worm’s males and females. | [117] |
| In vitro and in vivo efficacy of aqueous fraction and dichloromethane extracts against schistosomula, juvenile and adult worms of S. mansoni. | In vitro: Same as above In vivo: Single doses 40 and 200 mg/kg of B. trimera and PZQ 4 after 3 and 30 days p.i. and 60 p.i. |
In vitro: Similar results described. In vivo: B. trimera exhibits major schistosomicidal effects in vivo against immature and adult worms (significantly female worm, 68–75%, reduction and number of eggs/g in faeces); Significant reduction in relation to number and size of granulomas. | [118] | |
| Melatonin | Assessment protection against oxidative stress induced by schistosomiasis mansoni. | 3.55 mg/kg daily for 30 consecutive days starting from first day p.i. | Decreased in total leukocyte count: Markedly reduced the fibrotic areas, small diameter of granuloma with few collagen fiber depositions; ameliorate liver architecture and glycogen content. | [119] |
| Establish an immunization program using S. mansoni adult worm antigen and cercarial antigen alone or concurrently with Mel in attempt to enhance efficacy against infection in mice. | 30 μg/mL CAP or SWAP on first day and 20 μg/mL on 4th day p.i.; On 7th day all hamsters were infected. Mel same regimen as above. | Mel alone did not result decrease of worm burden reductions (CAP: 538%; CAP + Mel: 67.01%; SWAP: 56.4% and SWAP + Mel: 99.3%). Highly significant reductions in egg load in liver and alteration of oogram pattern: high percentage of immature eggs and few dead eggs. Improved the oxidative status in the immunized groups. No antibody response was observed in the groups immunized with SWAP + Mel while low antibody level was observed in CAP + Mel. | [120] | |
| Investigate oxidative processes in mice infected with S. mansoni | 10 mg/kg, 2 weeks after S. mansoni infection until end of experiment; or daily for 30 days | Mel did not restore glutathione levels (although were tendencies for that); Increase SOD activity (but not statistically significant); Reduction of AST levels; Reduction of granuloma formation and highly protective against pathological changes not only in liver but kidney; Mel has multiple direct and indirect antioxidant actions and its ability to stimulate antioxidative enzymes and mitochondrial oxidative phosphorylation. | [121] | |
| 4-Hydroxy-quinolin-2(1H)-one (BDHQ) | Evaluation potential activity on murine schistosomiasis. For that mice were sacrificed on different weeks p.i.: 3 (for schistosomula) and 6 (for adult worms) | BDHQ: Lower dose—10 mg/mL for consecutive days; Higher dose on same regimen; PZQ: 2 times of 500 mg/kg 2 consecutive days on different weeks. |
Antischistosomal activity against immature and mature worms; Destructive effects on the female and male genital systems; Antischistosomal activity may be due to its mixed cellular and humoral immunologic mechanisms, as demonstrated by the significant increase of serum levels of IgE and IFN-γ. | [122] |
| 4-Hydroxy-quinolin-2(1H)-one (BDHQ) | Evaluation of antioxidant and antigenotoxic effects alone or combined with PZQ. | PZQ, 0 or 500 mg/kg BDHQ, 600 mg/kg PZQ (250 mg/kg) + BDHQ (300 mg/kg) for 2 consecutive days |
BDHQ alone or combined resulted in highly significant reduction in total worm burden (7 weeks p.i. PZQ: 86.37%, BDHQ: 79.22%; PZQ + BDHQ: 91.84%; 9 weeks PZQ: 94.72%, BDHQ: 92.32%; PZQ + BDHQ: 95.54%), associated with significant reduction in the hepatic tissue egg load; Drugs alone reduced the granuloma size and inflammatory cells. These parameters were improved with combine regimen; Significant decrease in MDA level accompanied with highly increase in NOx level with combine regimen, in addition to increase in the activities of both SOD and CAT; Remarkable significant decrease in % DNA fragmentation reaching a level close to control; These suggest a synergistic action attributed to different mechanism of action of both drugs that achieved the same or higher levels of efficacy using smaller doses of either agent. | [123] |
| Sylimarin | Assessment of parasitological and biochemical parameters on S. mansoni infection in mice. | 10, 20 or 25 doses of 10 mg/kg Syl suspended on carboxymethyl-cellulose at 55 days p.i. | Did not show antischistosomal activity; Reduced granulomatous and hepatic fibrosis. At acute schistosomiasis may result in a mild course of murine schistosomiasis and minimize the deleterious effects. | [124] |
| Anti-inflammatory/antifibrotic effect alone and combined with PZQ. | Syl: —4th week p.i. (3 weeks before PZQ therapy) —12th week p.i. (5 weeks after PZQ); PZQ (7th week p.i.) Syl + PZQ |
Syl alone: Partial decrease of worm burden (26.55 and 39.39%) and decrease hepatic tissue egg load with an increase in percentage of dead ova; Modulation of granuloma size and conservation of hepatic GSH. PZQ: Complete eradication of worm, egg and alleviated liver inflammation and fibrosis; Combine regime: Improvement of liver function and histopathology whether acute and chronic infection may due to a combine action of anti-inflammatory, anti-fibrotic actions, in addition to the antioxidant properties of silymarin. Syl did not interfere or affect the antischistosomal activity of PZQ. Worm burden reduction 97–100%. |
[125] | |
| A. sativum | Antischistosomal activity against S. japonicum cercariae in vitro and in vivo. | In vitro: 10−2 to 10−6 (v/v) concentration. In vivo: Pre-treated with garlic, then mice were infected. |
Garlic oil displays marked activity agaisnts S. japonicum cercariae and may be used as agent to prevent S. japonicum (pre-exposure garlic oil at 10−4 and high showed total inhibition of infection). | [126] |
| A. sativum | Assess potency and the immunomodulatory response in enhancing the host immune system caused by S. mansoni in mice at different stages of worm. | 100 mg/kg body weight from 1 to 7 days p.i., 14 to 21 or 1 to 42 days p.i. | Morphologic alterations in the parasite tegument; significant decrease in worm burden, hepatic and inestinal ova count. Decline in granuloma number and diameter; Reduction in serum TNF-α, ICAM-1, IgG and IgM after 7 and 42 days p.i.; garlic oil enhance host immune system. | [127] |
| Ability of both oils to offser infectivity as well as metabolic disturbances induced by S. mansoni infection | 5 mL/kg body daily separately for 8 weeks on healthy control and infected groups. On infected groups oil were given 24 h p.i. | Reduced worm burden (garlic: 67.56% and onion: 75.97%) and ova count; normalized liver functions enzymes; effect may be induced by improving the immunological host immune system and their antioxidant activities. | [128] | |
| A. sativum+ A. cepa | Effect of both oils alone and mixed or concurrently with PZQ on biochemical parameters of experimentally infected S. mansoni mice. |
A. sativum or A. Cepa, 2 g/100 g body weight daily for 45 consecutive days. PZQ: 500 mg/kg bw on 2 successive days 45 days p.i. |
Significant reduction in worm burden (PZQ: 95.8%; onion: 66.29%; PZQ + onion: 99.1%; garlic: 73.41; garlic + PZQ: 99.3%; garlic + onion: 74.63; garlic + onion + PZQ: 99.7%); Reduction hepatic and intestinal eggs and oogram count; Suppression in granuloma tissue formation and diminutive histopathological changes; Improvement of liver architecture and attenuated the decrease of tissue antioxidant enzymes | [129] |
| Antischistosomal activity in vitro against S. mansoni miracidia, cercariae, schistosomula and adult worm. Effect in vivo on lipid peroxidase and antioxidant enzymes. | In vitro: 0.5–5 ppm In vivo: Same described above. |
Lethal effect of both antioxidant against all developmental stages; Inhibition of coupling; Powerful reducing capacity demonstrated in DPHH radical scavenging and NO; Both plants enhance host antioxidant system indicated by lowering in lipid peroxide and stimulation of SOD, CAT, GR, TrxR and SDH enzyme levels which could turn render parasite vulnerable. | [130] | |
| Antischistosomal activity against miracidia, cercariae and adult worms in vitro. Effect on some antioxidants enzymes. | In vitro: Serial concentrations (0.5–5 ppm) for miracidia and cercariae. Adult worms, 10–110 ppm. | Antischistosomal activity against miracida and cercariae; Separation of coupled worms; Inhibition of egg laying by adult female worms; Significant inhibition of parasitic antioxidant enzymes (SOD, GR and GPX) and enzymes glucose metabolism (HK and G-6-PDH), higher in males than females. | [131] | |
| Nigella sativa | Effect in protection against oxidative stress in experimentally infected mice with S. mansoni. | N. sativa oil (1.14 g/kg orally) for 30 consecutive days from first day p.i. | No suppressive effect on granuloma formation in intestine; Did not improve the liver architecture; Noticeable degree of protection represented in less severe pathological changes, particularly the frequency of inflammatory reactions. | [126] |
| Study effect the oil on liver functions and antioxidant ability on experimentally infected mice with S. mansoni. | 2.5 and 5 mL/kg orally either alone or in combination with PZQ (500 mg/kg for 2 consecutive days) | N. sativa alone: Reduce the number of S. mansoni worms in the liver; Total worm burden: 22% e 32%, respectively, while PZQ: 98%; Decreased total number of ova deposited; Increased the number of dead ova; Reduced the granuloma markedly; Partially correct alterations in serum levels of ALT, GGT, activity as well as the Ab content. Failed in the liver restore either LPD and GSH content or LDH (lactate dehydrogenase) and SOD activity to normal level. N. sativa + PZQ: Improved most parameters with most prominent effect was further lowering in dead ova number over that produced by PZQ. Total worm burden: 98% and 99%. | [132] | |
| Nigella sativa | Investigate immune mechanism possibly involved in the amelioration of histopathological changes in liver of S. mansoni infected mice treated alone or in combination with ART or PZQ. | N. sativa: orally with 0.2 mg/kg of body weight for 4 weeks starting from 1st day p.i. ART: intramuscularly single dose of 300 mg/kg of body weight after 49 days p.i. PZQ: 500 mg/kg for 2 consecutive days | N. sativa as well as the combination of ART or PZQ resulted in significant increase in IL-2, IL-12 and TNF-α activities in S. mansoni infected mice as well as treatment of NS in non-infected. N. sativa in combination with ART or PZQ accelerate healing pathological granulomatous lesions of liver architecture and improved host immunity by stimulating cytokines. | [133] |
| Antischistosomal activity and antioxidant effects of NS alone or combined with garlic extracts on experimentally S. mansoni infected mice. | Garlic extract 125 mg/kg p.i. and NS oil 0.2 mg/kg alone or combine for successive 28 days, starting 1st day p.i. | All treatment regimens significantly affected oogram pattern: treatment with compounds alone resulted in reduction of percentage of mature eggs while combine regimen resulted in increase of percentage of dead eggs. Administration of garlic extract prevent GSH depletion on infected mice. Combine regimen had more significant effect on serum enzymes (AST and ALP). | [134] | |
| Curcumin | Assess curative effect of oil extract in liver cells of S. mansoni infected mice in compaison to PZQ | PZQ: 500 mg/kg by 2 consecutive days Extract: 300 mg/kg bw after one month p.i., twice a week for 2 months |
Curcumin normalize the concentration of protein, glucose, AMP-deaminase and adenosine deaminase which were altered by infection Lowered pyruvate kinase level while PZQ induce more elevation; More potent rather PZQ in reducing egg count but no lowering worm burden. Most likely, antifecundity effect of curcumin might be involve in impairment or adult worms. | [135] |
| Evaluation of schistosomicidal activity in vivo and immunomodulation of granulomatous inflammation and liver pathology in acute S. mansoni infection. | Total dose 400 mg/kg bw divided into 16 injections (2 injections per week for 8 consecutive weeks) starting from the first week of infection. | Effective in reducing worm (44.4%) and tissue-egg burdens; Reduction granuloma volume and liver collagen (79%); Restore hepatic enzymes activities to normal levels and enhanced catalase activity; Low serum level of both IL-12 and TNF-α; Augmented specific IgG and IgG1 responses against both SWAP and SEA.; It modulates cellular and humoral responses. | [136] | |
| Evaluation its role on induction of apoptosis and oxidative stress in couples of adult S. mansoni worms in vitro | 1.56 to 100 μM incubated for 6, 12 or 24 h. | Significantly decreases the viability of adult female and male worms; Induce separation of couples and morphological alteration on mitochondria; Induce formation of SOD and increase its activity in adult worms; Alters several oxidative stress parameters in adult worms such decrease of GST, GR and GPX culminating in the oxidation of protein: Generates oxidative stress followed by an apoptotic-like event in adult worms, which ultimate leads to their dead. | [137] | |
| β-carotene | Evaluation the protective effect on experimentally S. mansoni infected mice and on major enzymes activities involved in liver redox. | PZQ, 7 weeks p.i., 500 mg/kg (full dose) or PZQ ED50 74.64 mg/kg βC, 2.7 mg/kg, 1 week before infection. βC + PZQ ED50 as mentioned |
Produced significant reduction in worm burden (total number of worms: PZQ: 11.57 ± 0.59; PZQ (full dose): 0.46 ± 0.14; βC: 17.64 ± 1.11; βC + PZQ: 8.38 ± 0.51) accompanied with increase of dead ova and decrease in percentage of mature ova; reduced liver granuloma diameter. Combined regimen improved these parameters. Combined regimen improved the effect of antioxidant enzymes (as GPX and GST) and increase serum ALT and GGT. βC has protective effects against liver fibrosis which may be due to ability to encounter or minimize the formation of schistosomal products. | [138] |
| N-Acetyl-cysteine | Study immunopathological changes in murine schistosomiasis alone or in combination with PZQ. | NAC (200 mg/kg/day on 1st day after infection for acute phase; On 45th for the intermediate; 59 and 75th for chronic phases. PZQ (100 mg/kg) from 45th to 49th day p.i. |
NAC alone did not present any schistosomicidal activity; animals treated with NAC and/or PZQ showed a reduction in the size of granulomas and those treated with NAC exhibited a lower degree of fibrosis. NAC functions as a direct scavenger of NO and peroxinitrite which are related to reductions of IFN-γ levels and increasing of IL-10 synthesis; Induce an immunomodulatory effect and reduce liver damage during granulomatous inflammation. | [139] |
| Investigate ability of NAC to enhance potential of ART against adult S. mansoni worms and evaluates protective role on oxidative stress. | NAC-300 mg/kg 5 days a week for 4 weeks ART-300 mg/kg 7 weeks p.i. NAC + ART (as described) |
Combine regimen approximately recovered levels of serum enzymes, content of GSH and activities. Decrease the total number of worms and hepatic ova count. ART alone produce valuable modulations in the hepatic activities; NAC may prevent experimental liver injury by modulating and enhancing GSH content and GSH-dependent antioxidant enzyme activities. Total worms: ART: 7.6 ± 1.5; NAC: 17.7 ± 1.5; NAC + ART: 3.3 ± 1.1. | [140] |
PZQ: praziquantel; Resv-Resveratrol; Mel-melatonin; BDHQ: 4-hydroxy-quinolin-2(1H)-one; ART: artemether; NS: Nigella sativa; βC: β-carotene; NAC: N-acetyl-cysteine; AS: aspidin; FAA: flavaspidic acid; MbA: methylene-bis-aspidinol; DA: desaspidin; Syl: sylimarin; p.i.: post-infection bw: body weight; GSH: glutathione; GR: glutathione reductase; SOD: superoxide dismutase; GGT: gamma-glutamyl transferase; CAT: catalase; TrxR: thioredoxin reductase; SDH: succinate dehydrogenase; GPx: glutathione peroxidase; HK: hexokinase; G-6-PDH: glucose-6-phosphate dehydrogenase; DPHH: 1,1-diphenyl-2-picrylhydrazyl; NOx: nitrogen oxide; IgG: immunoglobin G; IgE: immunoglobin E; IgM: immunoglobin M; IL-2: interleukin-2; IL-10: interleukin-10; IL-12: interleukin-12; IFN-γ: interferon gamma; TNF-α: tumor necrosis factor α; ICAM-1: intracellular adhesion molecule; ALA: alanine aminotransferase; AST: aspartate transaminase; MDA: malondialdehyde; LPD: lipoamide dehydrogenase; LDH: lactate dehydrogenase; ALP: alkaline phosphatase; AMP: adenosine monophosphate; SEA: soluble egg antigen; CAP: cercarial antigen preparation; SWAP: soluble worm antigen preparation.