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Am. J. Trop. Med. Hyg., 79(6), 2008, pp. 823-825
Copyright © 2008 by The American Society of Tropical Medicine and Hygiene

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SHORT REPORT


Failure of Two Distinct Anti-apoptotic Approaches to Reduce Mortality in Experimental Cerebral Malaria

Andrew J. Helmers, Fiona E. Lovegrove, John M. Harlan, Kevin C. Kain{dagger}, AND W. Conrad Liles*,{dagger}
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Washington, Seattle, Washington; Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada

 

ABSTRACT

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.

Received May 22, 2008. Accepted for publication August 12, 2008.

Financial support: This work was supported by grants from the Canadian Institutes of Health Research (Team Grant in Malaria CTP 79842 [KCK, Principal Investigator] and MT-13721 [KCK]), and by Genome Canada through the Ontario Genomics Institute. AJH is supported by a CIHR research Studentship, FEL is supported by a CIHR MD/PhD Studentship, KCK by a CIHR Canada Research Chair in Molecular Parasitology, and WCL by a CIHR Canada Research Chair in Infectious Diseases and Inflammation.

* Address correspondence to W. Conrad Liles, Toronto General Hospital 13E 214, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. E-mail: Conrad.liles{at}uhn.on.ca

{dagger} These authors contributed equally to this work.

Authors’ addresses: Andrew J. Helmers, Fiona E. Lovegrove, Kevin C. Kain, and W. Conrad Liles, Toronto General Hospital 13E 214, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada, Tel: 416-340-4800 ext. 3535, Fax: 416-340-3357, E-mail: kevin.kain{at}uhn.on.ca. John M. Harlan, Box 357710, University of Washington, Seattle, WA 98195-7710, Tel: 206-543-3360, Fax: 206-543-3560.






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