title: Investigation of hydrogen sulfide gas as a treatment against P. falciparum, murine cerebral malaria, and the importance of thiolation state in the development of cerebral malaria.
abstract: BACKGROUND
  Cerebral malaria (CM) is a potentially fatal cerebrovascular disease of complex pathogenesis caused by Plasmodium falciparum. Hydrogen sulfide (HS) is a physiological gas, similar to nitric oxide and carbon monoxide, involved in cellular metabolism, vascular tension, inflammation, and cell death. HS treatment has shown promising results as a therapy for cardio- and neuro- pathology. This study investigates the effects of fast (NaHS) and slow (GYY4137) HS-releasing drugs on the growth and metabolism of P. falciparum and the development of P. berghei ANKA CM. Moreover, we investigate the role of free plasma thiols and cell surface thiols in the pathogenesis of CM.
  
  
  METHODS
  P. falciparum was cultured in vitro with varying doses of HS releasing drugs compared with artesunate. Growth and metabolism were quantified. C57Bl/6 mice were infected with P. berghei ANKA and were treated with varying doses and regimes of HS-releasing drugs. Free plasma thiols and cell surface thiols were quantified in CM mice and age-matched healthy controls.
  
  
  RESULTS
  HS-releasing drugs significantly and dose-dependently inhibited P. falciparum growth and metabolism. Treatment of CM did not affect P. berghei growth, or development of CM. Interestingly, CM was associated with lower free plasma thiols, reduced leukocyte+erythrocyte cell surface thiols (infection day 3), and markedly (5-fold) increased platelet cell surface thiols (infection day 7).
  
  
  CONCLUSIONS
  HS inhibits P. falciparum growth and metabolism in vitro. Reduction in free plasma thiols, cell surface thiols and a marked increase in platelet cell surface thiols are associated with development of CM. HS drugs were not effective in vivo against murine CM.
authors.affiliation: Centre for Medical Parasitology, Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, Denmark. briandellavalle@gmail.com
authors.forename: Brian
authors.initials: B
authors.lastname: DellaValle
authors.forename: Trine
authors.initials: T
authors.lastname: Staalsoe
authors.forename: Jørgen Anders Lindholm
authors.initials: JA
authors.lastname: Kurtzhals
authors.forename: Casper
authors.initials: C
authors.lastname: Hempel
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D001792:Blood Platelets / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D016779:Malaria, Cerebral / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013045:Species Specificity; D013438:Sulfhydryl Compounds / Q000097:blood* / Q000737:chemistry; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D013438:Sulfhydryl Compounds; D013440:Sulfides; D000077332:Artesunate; C025451:sodium bisulfide; D006862:Hydrogen Sulfide
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