PPARγ Agonists Improve Survival and Neurocognitive Outcomes in Experimental Cerebral Malaria and Induce Neuroprotective Pathways in Human Malaria

Lena Serghides,Chloe R Mcdonald,Cheryl Cui,Miriam Friedel,Ziyue Lu,John G Sled,Howard T J Mount,Kevin C Kain,Keith T Ho,Eleanor M Riley

doi:10.1371/journal.ppat.1003980

Abstract

Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ 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 brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM.

Highlights

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that is associated with high mortality rates despite potent anti-anti-malarial therapy [1,2]
We demonstrate that Peroxisome proliferators-activated receptor gamma (PPARc) agonists, when administered with anti-malarials, protected mice from developing brain atrophy and neurocognitive impairment
Our findings suggest that PPARc agonists may be valuable in the treatment and prevention of CM-induced neurocognitive injury, and support the testing of PPARc agonists in patients with CM

Summary

Introduction

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that is associated with high mortality rates despite potent anti-anti-malarial therapy [1,2]. While it was long believed that the majority of children surviving CM were left neurologically intact, recent studies have challenged this assumption and provided evidence that many CM survivors have long-term cognitive and neurological deficits [4,5,6]. Both parasite and host determinants contribute to the onset and neurological outcome of CM. Host innate immune responses to infection combined with sequestration of parasitized erythrocytes (PEs) in the microvasculature of the brain, result in dysregulated inflammation, endothelial activation and dysfunction, microvascular occlusion, vascular leak, and loss of blood-brain barrier (BBB) function and integrity [7]. In experimental models of CM (ECM), intravital microscopy studies have revealed that neurological signs in ECM are associated with dysfunction of the neuroimmunological BBB, including vascular leak from post-capillary venules [11]

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