title: Glucagon-like peptide-1 analogue, liraglutide, in experimental cerebral malaria: implications for the role of oxidative stress in cerebral malaria.
abstract: Cerebral malaria from Plasmodium falciparum infection is major cause of death in the tropics. The pathogenesis of the disease is complex and the contribution of reactive oxygen and nitrogen species (ROS/RNS) in the brain is incompletely understood. Insulinotropic glucagon-like peptide-1 (GLP-1) mimetics have potent neuroprotective effects in animal models of neuropathology associated with ROS/RNS dysfunction. This study investigates the effect of the GLP-1 analogue, liraglutide against the clinical outcome of experimental cerebral malaria (ECM) and Plasmodium falciparum growth. Furthermore the role of oxidative stress on ECM pathogenesis is evaluated.
  
  
  
  ECM was induced in Plasmodium berghei ANKA-infected C57Bl/6j mice. Infected Balb/c (non-cerebral malaria) and uninfected C57Bl/6j mice were included as controls. Mice were treated twice-daily with vehicle or liraglutide (200 μg/kg). ROS/RNS were quantified with in vivo imaging and further analyzed ex vivo. Brains were assayed for cAMP, activation of cAMP response element binding protein (CREB) and nitrate/nitrite. Plasmodium falciparum was cultivated in vitro with increasing doses of liraglutide and growth and metabolism were quantified.
  
  
  
  The development and progression of ECM was not affected by liraglutide. Indeed, although ROS/RNS were increased in peripheral organs, ROS/RNS generation was not present in the brain. Interestingly, CREB was activated in the ECM brain and may protect against ROS/RNS stress. Parasite growth was not adversely affected by liraglutide in mice or in P. falciparum cultures indicating safety should not be a concern in type-II diabetics in endemic regions.
  
  
  
  Despite the breadth of models where GLP-1 is neuroprotective, ECM was not affected by liraglutide providing important insight into the pathogenesis of ECM. Furthermore, ECM does not induce excess ROS/RNS in the brain potentially associated with activation of the CREB system.
authors.affiliation: Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark. briandellavalle@gmail.com.|Department of Biomedical Sciences, Biotech Research and Innovation Center, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. briandellavalle@gmail.com.|Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, Denmark. briandellavalle@gmail.com.
authors.forename: Brian
authors.initials: B
authors.lastname: DellaValle
authors.affiliation: Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark.|Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Casper
authors.initials: C
authors.lastname: Hempel
authors.affiliation: Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark.|Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Trine
authors.initials: T
authors.lastname: Staalsoe
authors.affiliation: Department of Biomedical Sciences, Biotech Research and Innovation Center, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Flemming Fryd
authors.initials: FF
authors.lastname: Johansen
authors.affiliation: Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark.|Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jørgen Anders Lindholm
authors.initials: JA
authors.lastname: Kurtzhals
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D054795:Incretins / Q000008:administration & dosage*; D000069450:Liraglutide / Q000008:administration & dosage*; D016779:Malaria, Cerebral / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress; D010962:Plasmodium berghei / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects; D026361:Reactive Nitrogen Species / Q000032:analysis; D017382:Reactive Oxygen Species / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D054795:Incretins; D018696:Neuroprotective Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D000069450:Liraglutide
keywords: CM; CREB; Cerebral malaria; GLP-1; Liraglutide; Oxidative stress; Plasmodium; ROS