Neuregulin-1 attenuates mortality associated with experimental cerebral malaria

Background: cerebral 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).methods: we 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.results: treatment 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.conclusions: this study suggests that nrg-1 attenuates ecm-associated brain inflammation and injuries and may represent a novel supportive therapy for the management of cm. © 2014 solomon et al.; licensee biomed central ltd.