Abstract
Despite appropriate anti-malarial treatment, cerebral malaria (CM)-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM) mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs) and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection) and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10) and increasing angiogenic factor (VEGF) production. Treatment with a combination of atorvastatin and artemether improved survival (100%) when compared with artemether monotherapy (70%), p<0.05. Thus, adjunctively reducing CXCL10 levels and inflammation by atorvastatin treatment during anti-malarial therapy may represent a novel approach to treating CM patients.
Highlights
Malaria caused by Plasmodium falciparum infection remains a leading cause of global morbidity and mortality
Our previous studies indicate that CXCL10 levels are remarkably elevated in plasma and cerebrospinal fluid of patients who died from cerebral malaria (CM) than those who survive the disease after treatment confirming the observation linking elevated CXCL10 in CM patients with poor prognosis [36,37,38]
These observations in human CM were confirmed in murine studies, which revealed that mice deficient in the CXCL10 gene were partially protected against murine experimental cerebral malaria (ECM) when infected with P. berghei ANKA [44]
Summary
Malaria caused by Plasmodium falciparum infection remains a leading cause of global morbidity and mortality. Despite appropriate anti-malarial treatment using quinine or artemisinin derivatives, CM mortalities remains high (approximately 30% in adults and 18% in children) while 25% of survivors experience long-term neurological and cognitive impairment [2,3,4,5,6]. These observations suggest that strategies targeting the elimination of parasites during CM pathogenesis may be insufficient to prevent post treatment neurological complication and death [7]
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