title: Neuregulin-1 attenuates mortality associated with experimental cerebral malaria.
abstract: 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.
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA. wsolomon@msm.edu.
authors.forename: Wesley
authors.initials: W
authors.lastname: Solomon
authors.forename: Nana O
authors.initials: NO
authors.lastname: Wilson
authors.forename: Leonard
authors.initials: L
authors.lastname: Anderson
authors.forename: Sidney
authors.initials: S
authors.lastname: Pitts
authors.forename: John
authors.initials: J
authors.lastname: Patrickson
authors.forename: Mingli
authors.initials: M
authors.lastname: Liu
authors.forename: Byron D
authors.initials: BD
authors.lastname: Ford
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Stiles
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000469:parasitology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D016779:Malaria, Cerebral / Q000150:complications / Q000188:drug therapy* / Q000401:mortality*; D051379:Mice; D008810:Mice, Inbred C57BL; D020890:Neuregulin-1 / Q000378:metabolism / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010962:Plasmodium berghei / Q000502:physiology
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D016207:Cytokines; D020890:Neuregulin-1; D018696:Neuroprotective Agents; D000077549:Artemether