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

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.

Figure 1

Survival curves. Kaplan-Meier curves for GA (circles) and vehicle (boxes) treated animals. Log-rank test yielded a statistically significant difference in the survival curves (p < 0.05).

Figure 2

Clinical course of the disease and parasitaemia levels. A: Cumulative SHIRPA score of GA (open bars) and vehicle (filled bars) treated animals on day 0, 5, 11 post-infection and in moribund animals with CM. B: Course of parasitaemia of GA (open bars) and vehicle (filled bars) treated animals. No significant differences were found in the respective values of the SHIRPA score and parasitaemia between GA and vehicle treated animals. Mean values and SEM are shown.

Figure 3

Histological analysis of microhaemorrhages, activated caspase-3 positive cells and brain sequestered leukocytes. Stereological analysis of histology of GA (open bars) and vehicle (filled bars) treated animals. A: Relative of microhaemorrhages affected brain area in moribund CM animals. B: Total number of parenchymal cells immunopositive for activated caspase-3 on day 4 post-infection and in moribund CM animals. C: Total number of brain sequestered leukocytes on day 4 post-infection and in moribund CM animals. Mean values and SEM are shown.

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.