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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

Experimental design for in vivo experiments.This scheme depicts schematically the studies conducted with S. mansoni-infected mice (n = 8) in this present work. Mice were treated daily (oral administration) with PZQ, EDLF or PZQ+EDLF since three days before animals were infected until eight days after infection. The untreated infected control group received only the vehicle solution used for 12 days. Animals that were untreated and uninfected (naive) were also run in parallel. Asterisks indicate when samples from animals were taken (sampling) to analyze the parameters indicated in the box. Animals were sacrificed at 8 weeks p.i., and the timeline of some major events in parasite life cycle and disease-related processes are indicated at the top of the scheme. See text for further details.
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pntd.0003893.g001: Experimental design for in vivo experiments.This scheme depicts schematically the studies conducted with S. mansoni-infected mice (n = 8) in this present work. Mice were treated daily (oral administration) with PZQ, EDLF or PZQ+EDLF since three days before animals were infected until eight days after infection. The untreated infected control group received only the vehicle solution used for 12 days. Animals that were untreated and uninfected (naive) were also run in parallel. Asterisks indicate when samples from animals were taken (sampling) to analyze the parameters indicated in the box. Animals were sacrificed at 8 weeks p.i., and the timeline of some major events in parasite life cycle and disease-related processes are indicated at the top of the scheme. See text for further details.

Mentions: A total of forty 6-week-old female SPF Swiss CD1 mice from Charles River laboratory Spain (CRIFFA S.A., Barcelona), weighing 16–25 g, were infected by abdominal percutaneous exposure to 150 S. mansoni cercariae per animal [48], and randomly allocated into five experimental groups (8 animals per group) as follows: naive, untreated and uninfected; infected untreated; PZQ, treated with PZQ and infected; EDLF, treated with EDLF and infected; PZQ+EDLF, treated with PZQ + EDLF and infected. Mice were treated daily, since three days before animals were infected until eight days after infection, with PZQ (100 mg/kg/day), EDLF (45 mg/kg/day) and the combination PZQ+EDLF with the same individual drug doses, orally administered. The experimental design followed is shown in Fig 1. The infected untreated control group received only the vehicle solution used for 12 days.


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)

Experimental design for in vivo experiments.This scheme depicts schematically the studies conducted with S. mansoni-infected mice (n = 8) in this present work. Mice were treated daily (oral administration) with PZQ, EDLF or PZQ+EDLF since three days before animals were infected until eight days after infection. The untreated infected control group received only the vehicle solution used for 12 days. Animals that were untreated and uninfected (naive) were also run in parallel. Asterisks indicate when samples from animals were taken (sampling) to analyze the parameters indicated in the box. Animals were sacrificed at 8 weeks p.i., and the timeline of some major events in parasite life cycle and disease-related processes are indicated at the top of the scheme. See text for further details.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003893.g001: Experimental design for in vivo experiments.This scheme depicts schematically the studies conducted with S. mansoni-infected mice (n = 8) in this present work. Mice were treated daily (oral administration) with PZQ, EDLF or PZQ+EDLF since three days before animals were infected until eight days after infection. The untreated infected control group received only the vehicle solution used for 12 days. Animals that were untreated and uninfected (naive) were also run in parallel. Asterisks indicate when samples from animals were taken (sampling) to analyze the parameters indicated in the box. Animals were sacrificed at 8 weeks p.i., and the timeline of some major events in parasite life cycle and disease-related processes are indicated at the top of the scheme. See text for further details.
Mentions: A total of forty 6-week-old female SPF Swiss CD1 mice from Charles River laboratory Spain (CRIFFA S.A., Barcelona), weighing 16–25 g, were infected by abdominal percutaneous exposure to 150 S. mansoni cercariae per animal [48], and randomly allocated into five experimental groups (8 animals per group) as follows: naive, untreated and uninfected; infected untreated; PZQ, treated with PZQ and infected; EDLF, treated with EDLF and infected; PZQ+EDLF, treated with PZQ + EDLF and infected. Mice were treated daily, since three days before animals were infected until eight days after infection, with PZQ (100 mg/kg/day), EDLF (45 mg/kg/day) and the combination PZQ+EDLF with the same individual drug doses, orally administered. The experimental design followed is shown in Fig 1. The infected untreated control group received only the vehicle solution used for 12 days.

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