Project Lead(s): Lena Serghides
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that is associated with high mortality rates, despite potent anti-malarial therapy.
Studies show CM survivors have long-term cognitive and neurological damage if treated with only the current gold standard treatment of malaria.
Adjunctive therapies, aimed at modifying the pathophysiological processes of malaria infection, have been investigated as a way to improve outcomes, albeit with limited success to date.
The objective of this project was to assess and design a therapeutic strategy that would protect the brain from neurological damage in CM cases.
Because PPARγ agonist drugs have anti-inflammatory and anti-oxidant properties, the team explored adding a PPARγ agonist drug as an adjunct therapy to standard malaria treatment and then evaluated the the effect in mice.
Rosiglitazone was selected as the drug of choice. Mice displaying signs of CM were treated with an anti-malarial (artesunate) plus either placebo or rosiglitazone.
The study extended these findings to a relevant human population by examining the levels of angiopoietin (Ang)-1, Ang-2, and brain-derived neurotrophic factor (BDNF) in plasma banked from malaria patients that had participated in an earlier randomized double-blind placebo controlled trial of rosiglitazone adjunctive therapy.
Results showed that rosiglitazone therapy resulted in improved survival and long-term neurocognitive performance in experimental models of CM, and was associated with the induction of neuroprotective pathways.
Compared to anti-malarial therapy alone, rosiglitazone adjunctive therapy administered to mice at the onset of CM signs was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase, and the neurotrophic factors BDNF and nerve growth factor (NGF) in the brains of infected mice. Mice treated with rosiglitazone were protected from the brain atrophy experienced by mice that received anti-malarials alone.
Evaluation of the banked blood showed significantly lower Ang-2 to Ang-1 ratio, which implies greater blood-brain barrier stability, and higher levels of the neuroprotective marker BDNF in the rosiglitazone arm, suggesting that rosiglitazone would have the same effect in humans as it has in mice.
The promising results achieved in the lab were published in PLOS Pathogens. A randomised placebo-controlled trial of rosiglitazone adjunctive therapy in children with cerebral malaria followed in Mozambique, funded by the Canadian Institutes of Health Research (CIHR).