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Inhibition of Granulomatous Inflammation and Prophylactic Treatment of Schistosomiasis with a Combination of Edelfosine and Praziquantel.

Yepes E, Varela-M RE, López-Abán J, Rojas-Caraballo J, Muro A, Mollinedo F - PLoS Negl Trop Dis (2015)

Bottom Line: Using in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity.The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals.Taken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.

View Article: PubMed Central - PubMed

Affiliation: IBSAL-CIETUS (Instituto de Investigación Biomédica de Salamanca-Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain; Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.

ABSTRACT

Background: Schistosomiasis is the third most devastating tropical disease worldwide caused by blood flukes of the genus Schistosoma. This parasitic disease is due to immunologic reactions to Schistosoma eggs trapped in tissues. Egg-released antigens stimulate tissue-destructive inflammatory and granulomatous reactions, involving different immune cell populations, including T cells and granulocytes. Granulomas lead to collagen fibers deposition and fibrosis, resulting in organ damage. Praziquantel (PZQ) is the drug of choice for treating all species of schistosomes. However, PZQ kills only adult Schistosoma worms, not immature stages. The inability of PZQ to abort early infection or prevent re-infection, and the lack of prophylactic effect prompt the need for novel drugs and strategies for the prevention of schistosomiasis.

Methodology/principal findings: Using in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity. The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals.

Conclusions/significance: Taken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.

No MeSH data available.


Related in: MedlinePlus

Effect on adult male and female worm burdens after PZQ, EDLF and PZQ+EDLF prophylactic treatments in mice infected with S. mansoni.Mice were treated by oral administration of 100 mg/kg/day PZQ, 45 mg/kg/day EDLF or PZQ+EDLF as prophylactic treatments for S. mansoni infection as shown in Materials and Methods. Infected untreated (untreated) mice were treated with vehicle. Each point represents data from an individual treated or infected untreated mouse. Horizontal bars indicate mean values. Significance (p) values with respect to infected untreated mice are indicated. The means ± SEM (n = 8) for each experimental condition are as follows: female (untreated: 20.38 ± 1.36; PZQ: 13.75 ± 2.29; EDLF: 11.25 ± 2.23; PZQ+EDLF: 10.38 ± 2.26) and male (untreated: 21.75 ± 1.49; PZQ: 14.25 ± 2.44; EDLF: 10.88 ± 2.03; PZQ+EDLF: 8.62 ± 1.76).
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pntd.0003893.g003: Effect on adult male and female worm burdens after PZQ, EDLF and PZQ+EDLF prophylactic treatments in mice infected with S. mansoni.Mice were treated by oral administration of 100 mg/kg/day PZQ, 45 mg/kg/day EDLF or PZQ+EDLF as prophylactic treatments for S. mansoni infection as shown in Materials and Methods. Infected untreated (untreated) mice were treated with vehicle. Each point represents data from an individual treated or infected untreated mouse. Horizontal bars indicate mean values. Significance (p) values with respect to infected untreated mice are indicated. The means ± SEM (n = 8) for each experimental condition are as follows: female (untreated: 20.38 ± 1.36; PZQ: 13.75 ± 2.29; EDLF: 11.25 ± 2.23; PZQ+EDLF: 10.38 ± 2.26) and male (untreated: 21.75 ± 1.49; PZQ: 14.25 ± 2.44; EDLF: 10.88 ± 2.03; PZQ+EDLF: 8.62 ± 1.76).

Mentions: In order to study the efficacy of EDLF in a prophylactic setting for schistosomiasis, we treated four different cohorts of CD1 mice with PZQ (100 mg/kg/day), EDLF (45 mg/kg/day), PZQ+EDLF and only vehicle (infected untreated control group), since three days before until eight days after being infected with S. mansoni cercariae as indicated in Materials and Methods and Fig 1. Both PZQ and EDLF were orally administered, and live adult worm count from hepatic and portomesenteric veins as well as the size of hepatic granuloma, and the total number of eggs found in liver was determined after the eighth week of infection. All treatments reduced significantly the number of live worms as compared to infected untreated mice, with the groups treated with EDLF and PZQ+EDLF showing the highest decrease in worm count, even higher than that obtained by using PZQ alone (Fig 3).


Inhibition of Granulomatous Inflammation and Prophylactic Treatment of Schistosomiasis with a Combination of Edelfosine and Praziquantel.

Yepes E, Varela-M RE, López-Abán J, Rojas-Caraballo J, Muro A, Mollinedo F - PLoS Negl Trop Dis (2015)

Effect on adult male and female worm burdens after PZQ, EDLF and PZQ+EDLF prophylactic treatments in mice infected with S. mansoni.Mice were treated by oral administration of 100 mg/kg/day PZQ, 45 mg/kg/day EDLF or PZQ+EDLF as prophylactic treatments for S. mansoni infection as shown in Materials and Methods. Infected untreated (untreated) mice were treated with vehicle. Each point represents data from an individual treated or infected untreated mouse. Horizontal bars indicate mean values. Significance (p) values with respect to infected untreated mice are indicated. The means ± SEM (n = 8) for each experimental condition are as follows: female (untreated: 20.38 ± 1.36; PZQ: 13.75 ± 2.29; EDLF: 11.25 ± 2.23; PZQ+EDLF: 10.38 ± 2.26) and male (untreated: 21.75 ± 1.49; PZQ: 14.25 ± 2.44; EDLF: 10.88 ± 2.03; PZQ+EDLF: 8.62 ± 1.76).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507859&req=5

pntd.0003893.g003: Effect on adult male and female worm burdens after PZQ, EDLF and PZQ+EDLF prophylactic treatments in mice infected with S. mansoni.Mice were treated by oral administration of 100 mg/kg/day PZQ, 45 mg/kg/day EDLF or PZQ+EDLF as prophylactic treatments for S. mansoni infection as shown in Materials and Methods. Infected untreated (untreated) mice were treated with vehicle. Each point represents data from an individual treated or infected untreated mouse. Horizontal bars indicate mean values. Significance (p) values with respect to infected untreated mice are indicated. The means ± SEM (n = 8) for each experimental condition are as follows: female (untreated: 20.38 ± 1.36; PZQ: 13.75 ± 2.29; EDLF: 11.25 ± 2.23; PZQ+EDLF: 10.38 ± 2.26) and male (untreated: 21.75 ± 1.49; PZQ: 14.25 ± 2.44; EDLF: 10.88 ± 2.03; PZQ+EDLF: 8.62 ± 1.76).
Mentions: In order to study the efficacy of EDLF in a prophylactic setting for schistosomiasis, we treated four different cohorts of CD1 mice with PZQ (100 mg/kg/day), EDLF (45 mg/kg/day), PZQ+EDLF and only vehicle (infected untreated control group), since three days before until eight days after being infected with S. mansoni cercariae as indicated in Materials and Methods and Fig 1. Both PZQ and EDLF were orally administered, and live adult worm count from hepatic and portomesenteric veins as well as the size of hepatic granuloma, and the total number of eggs found in liver was determined after the eighth week of infection. All treatments reduced significantly the number of live worms as compared to infected untreated mice, with the groups treated with EDLF and PZQ+EDLF showing the highest decrease in worm count, even higher than that obtained by using PZQ alone (Fig 3).

Bottom Line: Using in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity.The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals.Taken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.

View Article: PubMed Central - PubMed

Affiliation: IBSAL-CIETUS (Instituto de Investigación Biomédica de Salamanca-Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain; Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.

ABSTRACT

Background: Schistosomiasis is the third most devastating tropical disease worldwide caused by blood flukes of the genus Schistosoma. This parasitic disease is due to immunologic reactions to Schistosoma eggs trapped in tissues. Egg-released antigens stimulate tissue-destructive inflammatory and granulomatous reactions, involving different immune cell populations, including T cells and granulocytes. Granulomas lead to collagen fibers deposition and fibrosis, resulting in organ damage. Praziquantel (PZQ) is the drug of choice for treating all species of schistosomes. However, PZQ kills only adult Schistosoma worms, not immature stages. The inability of PZQ to abort early infection or prevent re-infection, and the lack of prophylactic effect prompt the need for novel drugs and strategies for the prevention of schistosomiasis.

Methodology/principal findings: Using in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity. The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals.

Conclusions/significance: Taken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.

No MeSH data available.


Related in: MedlinePlus