title: The novel ETA receptor antagonist HJP-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative.
abstract: OBJECTIVE
  To investigate the association between vasculopathy and survival during experimental cerebral malaria (ECM), and to determine whether targeting the endothelin-1 (ET-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival.
  
  
  METHODS
  C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were randomly assigned to four groups: no treatment, artemether treated, ET(A) receptor antagonist (HJP-272) treated, or HJP-272 and artemether treated. The uninfected control mice were treated with HJP-272 and artemether. We analyzed survival, cerebral hemorrhage, weight change, blood glucose levels and parasitemia.
  
  
  RESULTS
  Our studies demonstrated decreased brain hemorrhage in PbA-infected (ECM) mice treated when HJP-272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one novel ET(A) receptor antagonist synthesized by our group, is used in conjunction with artemether, an anti-malarial agent. In addition, despite adversely affecting parasitemia and weight in non-artemether treated infected mice, HJP-272, seemed to confer some survival benefit when used as adjunctive therapy, though this did not reach significance.
  
  
  CONCLUSIONS
  Previous studies demonstrate that the endothelin pathway is associated with vasculopathy, neuronal injury and inflammation in ECM. As demonstrated here, components of the ET-1 pathway may be important targets for adjunctive therapy in ECM, and may help in preventing hemorrhage and in improving survival when used as adjunctive therapy during malaria infection. The data presented suggest that our novel agent, HJP-272, may ameliorate alterations in the vasculature which can potentially lead to inflammation, neurological dysfunction, and subsequent death in mice with ECM.
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States.
authors: Minxian
authors: M
authors: Dai
authors: Brandi
authors: B
authors: Freeman
authors: Fernando P
authors: FP
authors: Bruno
authors: Henry J
authors: HJ
authors: Shikani
authors: Herbert B
authors: HB
authors: Tanowitz
authors: Louis M
authors: LM
authors: Weiss
authors: Sandra E
authors: SE
authors: Reznik
authors: Ralph A
authors: RA
authors: Stephani
authors: Mahalia S
authors: MS
authors: Desruisseaux
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology*; D002543:Cerebral Hemorrhage / Q000469:parasitology / Q000517:prevention & control*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006912:Hydroxyquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D016779:Malaria, Cerebral / Q000150:complications / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D018512:Parasitemia / Q000188:drug therapy; D010962:Plasmodium berghei / Q000302:isolation & purification; D011897:Random Allocation; D013534:Survival
chemical_list: C532839:3-(3-carboxybenzyl)-1-((6-ethylbenzo(d)(1,3)dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid; D000962:Antimalarials; D037621:Artemisinins; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D006912:Hydroxyquinolines; D000077549:Artemether