Abstract
BackgroundCerebral Malaria (CM) is a diffuse encephalopathy caused by Plasmodium falciparum infection. Despite availability of antimalarial drugs, CM-associated mortality remains high at approximately 30% and a subset of survivors develop neurological and cognitive disabilities. While antimalarials are effective at clearing Plasmodium parasites they do little to protect against CM pathophysiology and parasite-induced brain inflammation that leads to seizures, coma and long-term neurological sequelae in CM patients. Thus, there is urgent need to explore therapeutics that can reduce or prevent CM pathogenesis and associated brain inflammation to improve survival. Neuregulin-1 (NRG-1) is a neurotrophic growth factor shown to protect against brain injury associated with acute ischemic stroke (AIS) and neurotoxin exposure. However, this drug has not been tested against CM-associated brain injury. Since CM-associated brain injuries and AIS share similar pathophysiological features, we hypothesized that NRG-1 will reduce or prevent neuroinflammation and brain damage as well as improve survival in mice with late-stage experimental cerebral malaria (ECM).MethodsWe tested the effects of NRG-1 on ECM-associated brain inflammation and mortality in P. berghei ANKA (PbA)-infected mice and compared to artemether (ARM) treatment; an antimalarial currently used in various combination therapies against malaria.ResultsTreatment with ARM (25 mg/kg/day) effectively cleared parasites and reduced mortality in PbA-infected mice by 82%. Remarkably, NRG-1 therapy (1.25 ng/kg/day) significantly improved survival against ECM by 73% despite increase in parasite burden within NRG-1-treated mice. Additionally, NRG-1 therapy reduced systemic and brain pro-inflammatory factors TNFalpha, IL-6, IL-1alpha and CXCL10 and enhanced anti-inflammatory factors, IL-5 and IL-13 while decreasing leukocyte accumulation in brain microvessels.ConclusionsThis study suggests that NRG-1 attenuates ECM-associated brain inflammation and injuries and may represent a novel supportive therapy for the management of CM.
Highlights
Cerebral Malaria (CM) is a diffuse encephalopathy caused by Plasmodium falciparum infection
NRG-1 therapy attenuates experimental cerebral malaria (ECM)-associated mortality To test whether NRG-1 improves survival from ECM, P. berghei ANKA (PbA)-infected C57BL/6 J mice were treated with recombinant human NRG-1 (1.25 ng/kg/day) or ARM (25 mg/kg/day)
ECM-associated mortality was observed between days 5 and 12 post infection in PbA-infected mice sham-treated with saline, with mortality between 30% and 100% (Figure 1A)
Summary
Cerebral Malaria (CM) is a diffuse encephalopathy caused by Plasmodium falciparum infection. Understanding immunopathogenic features such as brain inflammation and injury leading to fatal CM have led to the identification and development of small molecules or immunotherapeutics that may be used to stabilize the blood–brain barrier (BBB) and ameliorate CM-associated brain damage and mortality [12,13,14]. Most of these interventions administered as prophylactics to prevent development of neurological signs failed to reverse CM-associated brain injuries or resulted in minimal therapeutic benefit, whereas others were deleterious [13,14]. Interventions aimed at modulating the deleterious hyper-inflammatory response to malaria infection while protecting against brain damage will potentially bolster therapeutics against severe malaria
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