Failure of two distinct anti-apoptotic approaches to reduce mortality in experimental cerebral malaria.
Cerebral malaria is responsible for a high proportion of mortality in human Plasmodium falciparum infection. Previous studies have reported the presence of apoptosis in endothelial cells, astrocytes, neurons, and glial cells in experimental murine cerebral malaria caused by infection with Plasmodium berghei ANKA. Using this model, we tested two strategies, which have been shown to improve survival in murine models of sepsis: 1) treatment with z-VAD, a pancaspase inhibitor; and 2) overexpression of Bcl-2 using transgenic mice expressing human Bcl-2 (which prevents the release of apoptotic mediators from the mitochondria) from a myeloid cell promoter. Neither of these anti-apoptotic strategies, previously shown to provide therapeutic benefit in sepsis, improved survival in experimental cerebral malaria.
Helmers
Andrew J
AJ
Institute of Medical Science, McLaughlin-Rotman Centre for Global Health, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Lovegrove
Fiona E
FE
Harlan
John M
JM
Kain
Kevin C
KC
Liles
W Conrad
WC
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000627:therapeutic use*; D010962:Plasmodium berghei; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid