Limits...
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

Effects on granuloma size and parasite egg burdens in liver after prophylactic treatment of S. mansoni-infected mice with PZQ, EDLF and PZQ+EDLF treatments.(A) Representative hepatic granulomas of 8-week-infected drug-untreated and drug-treated mice. Photographs were taken at 10 x. (B) Granuloma diameter. The average values of the diameters of 25 granulomas measured in liver sections from 5 infected mice per group (5 granulomas per mouse) are shown. Each point represents the value for an individual mouse. Significance (p) values with respect to infected untreated mice are indicated. Statistical significance between the PZQ and PZQ+EDLF groups is also included. (*) p<0.05. The means ± SEM (n = 5) for each experimental condition are as follows: untreated: 620.4 ± 28.70; PZQ: 526.9 ± 15.95; EDLF: 276 ± 14.41; PZQ+EDLF: 264.9 ± 5.41. (C) Parasite egg burden in liver. Infected mice were treated with 100 mg/kg PZQ, 45 mg/kg EDLF, or PZQ+EDLF. Infected untreated mice were run in parallel. Compounds were administered orally as described in Materials and Methods, and the number of eggs in liver was determined as eggs per gram (epg). Each point represents data from an individual treated- or infected untreated mouse. Horizontal bars indicate average values. Significance (p) values with respect to infected untreated mice are shown. Statistical significance between the PZQ and PZQ+EDLF groups is also included. (*) p<0.05. The means ± SEM (n = 5) for each experimental condition are as follows: untreated: 17411 ± 2805; PZQ: 17094 ± 2368; EDLF: 13796 ± 1804; PZQ+EDLF: 7126 ± 1279).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4507859&req=5

pntd.0003893.g004: Effects on granuloma size and parasite egg burdens in liver after prophylactic treatment of S. mansoni-infected mice with PZQ, EDLF and PZQ+EDLF treatments.(A) Representative hepatic granulomas of 8-week-infected drug-untreated and drug-treated mice. Photographs were taken at 10 x. (B) Granuloma diameter. The average values of the diameters of 25 granulomas measured in liver sections from 5 infected mice per group (5 granulomas per mouse) are shown. Each point represents the value for an individual mouse. Significance (p) values with respect to infected untreated mice are indicated. Statistical significance between the PZQ and PZQ+EDLF groups is also included. (*) p<0.05. The means ± SEM (n = 5) for each experimental condition are as follows: untreated: 620.4 ± 28.70; PZQ: 526.9 ± 15.95; EDLF: 276 ± 14.41; PZQ+EDLF: 264.9 ± 5.41. (C) Parasite egg burden in liver. Infected mice were treated with 100 mg/kg PZQ, 45 mg/kg EDLF, or PZQ+EDLF. Infected untreated mice were run in parallel. Compounds were administered orally as described in Materials and Methods, and the number of eggs in liver was determined as eggs per gram (epg). Each point represents data from an individual treated- or infected untreated mouse. Horizontal bars indicate average values. Significance (p) values with respect to infected untreated mice are shown. Statistical significance between the PZQ and PZQ+EDLF groups is also included. (*) p<0.05. The means ± SEM (n = 5) for each experimental condition are as follows: untreated: 17411 ± 2805; PZQ: 17094 ± 2368; EDLF: 13796 ± 1804; PZQ+EDLF: 7126 ± 1279).

Mentions: Interestingly, following both macroscopic and microscopic histopathological examination, we observed a significant reduction in hepatic granuloma size in mice treated with PZQ, EDLF and PZQ+EDLF as compared to infected untreated mice, EDLF and PZQ+EDLF being the most efficient treatments in reducing granulomatous inflammation (Fig 4A and 4B).


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)

Effects on granuloma size and parasite egg burdens in liver after prophylactic treatment of S. mansoni-infected mice with PZQ, EDLF and PZQ+EDLF treatments.(A) Representative hepatic granulomas of 8-week-infected drug-untreated and drug-treated mice. Photographs were taken at 10 x. (B) Granuloma diameter. The average values of the diameters of 25 granulomas measured in liver sections from 5 infected mice per group (5 granulomas per mouse) are shown. Each point represents the value for an individual mouse. Significance (p) values with respect to infected untreated mice are indicated. Statistical significance between the PZQ and PZQ+EDLF groups is also included. (*) p<0.05. The means ± SEM (n = 5) for each experimental condition are as follows: untreated: 620.4 ± 28.70; PZQ: 526.9 ± 15.95; EDLF: 276 ± 14.41; PZQ+EDLF: 264.9 ± 5.41. (C) Parasite egg burden in liver. Infected mice were treated with 100 mg/kg PZQ, 45 mg/kg EDLF, or PZQ+EDLF. Infected untreated mice were run in parallel. Compounds were administered orally as described in Materials and Methods, and the number of eggs in liver was determined as eggs per gram (epg). Each point represents data from an individual treated- or infected untreated mouse. Horizontal bars indicate average values. Significance (p) values with respect to infected untreated mice are shown. Statistical significance between the PZQ and PZQ+EDLF groups is also included. (*) p<0.05. The means ± SEM (n = 5) for each experimental condition are as follows: untreated: 17411 ± 2805; PZQ: 17094 ± 2368; EDLF: 13796 ± 1804; PZQ+EDLF: 7126 ± 1279).
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003893.g004: Effects on granuloma size and parasite egg burdens in liver after prophylactic treatment of S. mansoni-infected mice with PZQ, EDLF and PZQ+EDLF treatments.(A) Representative hepatic granulomas of 8-week-infected drug-untreated and drug-treated mice. Photographs were taken at 10 x. (B) Granuloma diameter. The average values of the diameters of 25 granulomas measured in liver sections from 5 infected mice per group (5 granulomas per mouse) are shown. Each point represents the value for an individual mouse. Significance (p) values with respect to infected untreated mice are indicated. Statistical significance between the PZQ and PZQ+EDLF groups is also included. (*) p<0.05. The means ± SEM (n = 5) for each experimental condition are as follows: untreated: 620.4 ± 28.70; PZQ: 526.9 ± 15.95; EDLF: 276 ± 14.41; PZQ+EDLF: 264.9 ± 5.41. (C) Parasite egg burden in liver. Infected mice were treated with 100 mg/kg PZQ, 45 mg/kg EDLF, or PZQ+EDLF. Infected untreated mice were run in parallel. Compounds were administered orally as described in Materials and Methods, and the number of eggs in liver was determined as eggs per gram (epg). Each point represents data from an individual treated- or infected untreated mouse. Horizontal bars indicate average values. Significance (p) values with respect to infected untreated mice are shown. Statistical significance between the PZQ and PZQ+EDLF groups is also included. (*) p<0.05. The means ± SEM (n = 5) for each experimental condition are as follows: untreated: 17411 ± 2805; PZQ: 17094 ± 2368; EDLF: 13796 ± 1804; PZQ+EDLF: 7126 ± 1279).
Mentions: Interestingly, following both macroscopic and microscopic histopathological examination, we observed a significant reduction in hepatic granuloma size in mice treated with PZQ, EDLF and PZQ+EDLF as compared to infected untreated mice, EDLF and PZQ+EDLF being the most efficient treatments in reducing granulomatous inflammation (Fig 4A and 4B).

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