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Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study.

Lackner P, Part A, Burger C, Dietmann A, Broessner G, Helbok R, Reindl M, Schmutzhard E, Beer R - Malar. J. (2009)

Bottom Line: The drug had no effect on the course of parasitaemia.The mechanism of action seems to be an immunomodulatory effect since lower IFN-gamma levels were observed in treated animals in the early course of the disease (day 4 post-infection) which also led to a lower number of brain sequestered leukocytes in treated animals.No direct neuro-protective effect such as an inhibition of apoptosis or reduction of micro-bleedings in the brain was found.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. peter.lackner@i-med.ac.at

ABSTRACT

Background: Cerebral malaria (CM) is associated with high mortality and morbidity caused by a high rate of transient or persistent neurological sequelae. Studies on immunomodulatory and neuroprotective drugs as ancillary treatment in murine CM indicate promising potential. The current study was conducted to evaluate the efficacy of glatiramer acetate (GA), an immunomodulatory drug approved for the treatment of relapsing remitting multiple sclerosis, in preventing the death of C57Bl/6J mice infected with Plasmodium berghei ANKA.

Methods and results: GA treatment led to a statistically significant lower risk for developing CM (57.7% versus 84.6%) in treated animals. The drug had no effect on the course of parasitaemia. The mechanism of action seems to be an immunomodulatory effect since lower IFN-gamma levels were observed in treated animals in the early course of the disease (day 4 post-infection) which also led to a lower number of brain sequestered leukocytes in treated animals. No direct neuro-protective effect such as an inhibition of apoptosis or reduction of micro-bleedings in the brain was found.

Conclusion: These findings support the important role of the host immune response in the pathophysiology of murine CM and might lead to the development of new adjunctive treatment strategies.

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Related in: MedlinePlus

Cytokine levels in sera. Cytokine levels in sera at day 4, 11 post-infection and in moribund animals with CM (pg/ml). (A: Interferon-gamma, B: Interleukin-2, C: Interleukin-4, D: Interleukin-5, E: Tumor-necrosis factor-alpha). On day 4 post-infection GA treated animals showed a significantly lower level of IFN-gamma than vehicle treated animals (A; *, p < 0.05). IFN-gamma levels on day 4 were significantly higher than the levels in moribund animals or in animals on day 11 post-infection (A; p < 0.001). TNF-alpha levels on day 4 and in moribund animals were significantly lower than on day 11 post-infection (E; p < 0.001). IL-2, IL-4, IL-5 levels on day 4 were significantly lower than the levels in moribund animals or in animals on day 11 post-infection (B-D; p < 0.001). IL-5 levels in moribund animals were significantly lower than in animals on day 11 post-infection (D; p < 0.001). Mean values and SEM are shown.
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Figure 4: Cytokine levels in sera. Cytokine levels in sera at day 4, 11 post-infection and in moribund animals with CM (pg/ml). (A: Interferon-gamma, B: Interleukin-2, C: Interleukin-4, D: Interleukin-5, E: Tumor-necrosis factor-alpha). On day 4 post-infection GA treated animals showed a significantly lower level of IFN-gamma than vehicle treated animals (A; *, p < 0.05). IFN-gamma levels on day 4 were significantly higher than the levels in moribund animals or in animals on day 11 post-infection (A; p < 0.001). TNF-alpha levels on day 4 and in moribund animals were significantly lower than on day 11 post-infection (E; p < 0.001). IL-2, IL-4, IL-5 levels on day 4 were significantly lower than the levels in moribund animals or in animals on day 11 post-infection (B-D; p < 0.001). IL-5 levels in moribund animals were significantly lower than in animals on day 11 post-infection (D; p < 0.001). Mean values and SEM are shown.

Mentions: The immuno-phenotype of animals was determined on day 4, in moribund CM animals, and on day 11 post infection in NCM animals by measuring 5 different cytokines in sera. On day 4 post-infection GA treated animals showed a significantly lower level of IFN-gamma (p < 0.05, Figure 4A). There were no significant differences in the levels of IL-2, IL-4, IL-5 or TNF-alpha (Figure 4B, C, D, E) between the treatment groups. IFN-gamma levels on day 4 were significantly higher than the levels in moribund animals or in animals on day 11 post-infection (Figure 4A, p < 0.001, Bonferroni corrected). TNF-alpha levels on day 4 and in moribund animals were significantly lower than on day 11 post-infection (Figure 4E, p < 0.001, Bonferroni corrected). IL-2, IL-4, IL-5 levels on day 4 were significantly lower than the levels in moribund animals or in animals on day 11 post-infection (Figure 4B, C, D, p < 0.001, Bonferroni corrected). IL-5 levels in moribund animals were significantly lower than in animals on day 11 post infection (Figure 4D, p < 0.001, Bonferroni corrected).


Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study.

Lackner P, Part A, Burger C, Dietmann A, Broessner G, Helbok R, Reindl M, Schmutzhard E, Beer R - Malar. J. (2009)

Cytokine levels in sera. Cytokine levels in sera at day 4, 11 post-infection and in moribund animals with CM (pg/ml). (A: Interferon-gamma, B: Interleukin-2, C: Interleukin-4, D: Interleukin-5, E: Tumor-necrosis factor-alpha). On day 4 post-infection GA treated animals showed a significantly lower level of IFN-gamma than vehicle treated animals (A; *, p < 0.05). IFN-gamma levels on day 4 were significantly higher than the levels in moribund animals or in animals on day 11 post-infection (A; p < 0.001). TNF-alpha levels on day 4 and in moribund animals were significantly lower than on day 11 post-infection (E; p < 0.001). IL-2, IL-4, IL-5 levels on day 4 were significantly lower than the levels in moribund animals or in animals on day 11 post-infection (B-D; p < 0.001). IL-5 levels in moribund animals were significantly lower than in animals on day 11 post-infection (D; p < 0.001). Mean values and SEM are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651188&req=5

Figure 4: Cytokine levels in sera. Cytokine levels in sera at day 4, 11 post-infection and in moribund animals with CM (pg/ml). (A: Interferon-gamma, B: Interleukin-2, C: Interleukin-4, D: Interleukin-5, E: Tumor-necrosis factor-alpha). On day 4 post-infection GA treated animals showed a significantly lower level of IFN-gamma than vehicle treated animals (A; *, p < 0.05). IFN-gamma levels on day 4 were significantly higher than the levels in moribund animals or in animals on day 11 post-infection (A; p < 0.001). TNF-alpha levels on day 4 and in moribund animals were significantly lower than on day 11 post-infection (E; p < 0.001). IL-2, IL-4, IL-5 levels on day 4 were significantly lower than the levels in moribund animals or in animals on day 11 post-infection (B-D; p < 0.001). IL-5 levels in moribund animals were significantly lower than in animals on day 11 post-infection (D; p < 0.001). Mean values and SEM are shown.
Mentions: The immuno-phenotype of animals was determined on day 4, in moribund CM animals, and on day 11 post infection in NCM animals by measuring 5 different cytokines in sera. On day 4 post-infection GA treated animals showed a significantly lower level of IFN-gamma (p < 0.05, Figure 4A). There were no significant differences in the levels of IL-2, IL-4, IL-5 or TNF-alpha (Figure 4B, C, D, E) between the treatment groups. IFN-gamma levels on day 4 were significantly higher than the levels in moribund animals or in animals on day 11 post-infection (Figure 4A, p < 0.001, Bonferroni corrected). TNF-alpha levels on day 4 and in moribund animals were significantly lower than on day 11 post-infection (Figure 4E, p < 0.001, Bonferroni corrected). IL-2, IL-4, IL-5 levels on day 4 were significantly lower than the levels in moribund animals or in animals on day 11 post-infection (Figure 4B, C, D, p < 0.001, Bonferroni corrected). IL-5 levels in moribund animals were significantly lower than in animals on day 11 post infection (Figure 4D, p < 0.001, Bonferroni corrected).

Bottom Line: The drug had no effect on the course of parasitaemia.The mechanism of action seems to be an immunomodulatory effect since lower IFN-gamma levels were observed in treated animals in the early course of the disease (day 4 post-infection) which also led to a lower number of brain sequestered leukocytes in treated animals.No direct neuro-protective effect such as an inhibition of apoptosis or reduction of micro-bleedings in the brain was found.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. peter.lackner@i-med.ac.at

ABSTRACT

Background: Cerebral malaria (CM) is associated with high mortality and morbidity caused by a high rate of transient or persistent neurological sequelae. Studies on immunomodulatory and neuroprotective drugs as ancillary treatment in murine CM indicate promising potential. The current study was conducted to evaluate the efficacy of glatiramer acetate (GA), an immunomodulatory drug approved for the treatment of relapsing remitting multiple sclerosis, in preventing the death of C57Bl/6J mice infected with Plasmodium berghei ANKA.

Methods and results: GA treatment led to a statistically significant lower risk for developing CM (57.7% versus 84.6%) in treated animals. The drug had no effect on the course of parasitaemia. The mechanism of action seems to be an immunomodulatory effect since lower IFN-gamma levels were observed in treated animals in the early course of the disease (day 4 post-infection) which also led to a lower number of brain sequestered leukocytes in treated animals. No direct neuro-protective effect such as an inhibition of apoptosis or reduction of micro-bleedings in the brain was found.

Conclusion: These findings support the important role of the host immune response in the pathophysiology of murine CM and might lead to the development of new adjunctive treatment strategies.

Show MeSH
Related in: MedlinePlus