Brain mitochondrial function in a murine model of cerebral malaria and the therapeutic effects of rhEPO.
Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection. The pathogenesis of CM is complex. Cerebral metabolic dysfunction is implicated in CM, which may be caused by both an impaired cerebral microcirculation and a dysregulated inflammatory response affecting cellular respiration of mitochondria. Recombinant human erythropoietin (rhEPO) is a promising new therapy that has been shown to reduce mortality in a mouse model of CM. In order to further elucidate the metabolic dysfunction in CM the objective of the present study was to assess brain mitochondrial respiratory function in CM with and without rhEPO treatment. The P. berghei ANKA - C57BL/6 murine model of CM was used. Mitochondrial respiration was analyzed in brain homogenates using high-resolution respirometry and a multiple substrate and inhibitor protocol. The animals were divided into four groups; infected injected with saline or with rhEPO, non-infected injected with saline or with rhEPO. Infected mice developed CM and treatment with rhEPO attenuated clinical signs of disease. There were no differences in respiratory parameters of brain mitochondria between infected and non-infected mice and no connection between disease severity and mitochondrial respiratory function. Treatment with rhEPO similarly had no effect on respiratory function. Thus cerebral metabolic dysfunction in CM does not seem to be directly linked to altered mitochondrial respiratory capacity as analyzed in brain homogenates ex vivo. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.
Mitochondrial Pathophysiology Unit, Department of Clinical Sciences, Lund University, BMC A13, 221 84 Lund, Sweden. michael.karlsson@med.lu.se
Michael
M
Karlsson
Casper
C
Hempel
Fredrik
F
Sjövall
Magnus J
MJ
Hansson
Jørgen A L
JA
Kurtzhals
Eskil
E
Elmér
D000818:Animals; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011994:Recombinant Proteins / Q000494:pharmacology
D011994:Recombinant Proteins; D004921:Erythropoietin