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

Granulocyte analysis in drug treated- and untreated-mice.Blood samples were analyzed for neutrophil, eosinophil and basophil counts in uninfected-untreated naive mice, infected untreated (untreated) mice and infected mice treated with PZQ, EDLF or PZQ+EDLF. Samples were taken at weeks 3 (A) and 8 (B) p.i. Data are shown as means ± SEM of eight mice. Asterisks represent statistical significance with respect to the infected untreated group. (*) p<0.05; (**) p<0.01; (***) p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003893.g008: Granulocyte analysis in drug treated- and untreated-mice.Blood samples were analyzed for neutrophil, eosinophil and basophil counts in uninfected-untreated naive mice, infected untreated (untreated) mice and infected mice treated with PZQ, EDLF or PZQ+EDLF. Samples were taken at weeks 3 (A) and 8 (B) p.i. Data are shown as means ± SEM of eight mice. Asterisks represent statistical significance with respect to the infected untreated group. (*) p<0.05; (**) p<0.01; (***) p<0.001.

Mentions: Here, we examined the levels of the above leukocyte types in peripheral blood in each experimental group at 3 and 8 weeks p.i. At week 3 p.i. we detected a significant reduction in the level of eosinophils in the group of mice treated with PZQ+EDLF when compared to the PZQ-treated group (Fig 8A), as well as a significant reduction in the levels of basophils in the mice treated with EDLF and PZQ+EDLF compared to the infected untreated group (Fig 8A). In the late stages of infection (week 8 p.i.), a significant increase in the number of neutrophils, eosinophils and basophils was found in the infected untreated mice compared to the naive non-infected animals (Fig 8B). Interestingly, we found a significant reduction in the levels of neutrophils, eosinophils and basophils in the groups of mice treated with EDLF and PZQ+EDLF as compared to the infected untreated group (Fig 8B). However, no significant changes were observed regarding the number of lymphocytes and monocytes in the three experimental groups as compared to infected untreated mice (S1 Table).


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)

Granulocyte analysis in drug treated- and untreated-mice.Blood samples were analyzed for neutrophil, eosinophil and basophil counts in uninfected-untreated naive mice, infected untreated (untreated) mice and infected mice treated with PZQ, EDLF or PZQ+EDLF. Samples were taken at weeks 3 (A) and 8 (B) p.i. Data are shown as means ± SEM of eight mice. Asterisks represent statistical significance with respect to the infected untreated group. (*) p<0.05; (**) p<0.01; (***) p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003893.g008: Granulocyte analysis in drug treated- and untreated-mice.Blood samples were analyzed for neutrophil, eosinophil and basophil counts in uninfected-untreated naive mice, infected untreated (untreated) mice and infected mice treated with PZQ, EDLF or PZQ+EDLF. Samples were taken at weeks 3 (A) and 8 (B) p.i. Data are shown as means ± SEM of eight mice. Asterisks represent statistical significance with respect to the infected untreated group. (*) p<0.05; (**) p<0.01; (***) p<0.001.
Mentions: Here, we examined the levels of the above leukocyte types in peripheral blood in each experimental group at 3 and 8 weeks p.i. At week 3 p.i. we detected a significant reduction in the level of eosinophils in the group of mice treated with PZQ+EDLF when compared to the PZQ-treated group (Fig 8A), as well as a significant reduction in the levels of basophils in the mice treated with EDLF and PZQ+EDLF compared to the infected untreated group (Fig 8A). In the late stages of infection (week 8 p.i.), a significant increase in the number of neutrophils, eosinophils and basophils was found in the infected untreated mice compared to the naive non-infected animals (Fig 8B). Interestingly, we found a significant reduction in the levels of neutrophils, eosinophils and basophils in the groups of mice treated with EDLF and PZQ+EDLF as compared to the infected untreated group (Fig 8B). However, no significant changes were observed regarding the number of lymphocytes and monocytes in the three experimental groups as compared to infected untreated mice (S1 Table).

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