Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria.
BACKGROUND
Cerebral malaria (CM) is an acute encephalopathy with increased pro-inflammatory cytokines, sequestration of parasitized erythrocytes and localized ischaemia. In children CM induces cognitive impairment in about 10% of the survivors. Erythropoietin (Epo) has - besides of its well known haematopoietic properties - significant anti-inflammatory, antioxidant and anti-apoptotic effects in various brain disorders. The neurobiological responses to exogenously injected Epo during murine CM were examined.


METHODS
Female C57BL/6j mice (4-6 weeks), infected with Plasmodium berghei ANKA, were treated with recombinant human Epo (rhEpo; 50-5000 U/kg/OD, i.p.) at different time points. The effect on survival was measured. Brain pathology was investigated by TUNEL (Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-digoxigenin nick end labelling), as a marker of apoptosis. Gene expression in brain tissue was measured by real time PCR.


RESULTS
Treatment with rhEpo increased survival in mice with CM in a dose- and time-dependent manner and reduced apoptotic cell death of neurons as well as the expression of pro-inflammatory cytokines in the brain. This neuroprotective effect appeared to be independent of the haematopoietic effect.


CONCLUSIONS
These results and its excellent safety profile in humans makes rhEpo a potential candidate for adjunct treatment of CM.
Wiese
Lothar
L
Center for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark. Wiese@dadlnet.dk
Hempel
Casper
C
Penkowa
Milena
M
Kirkby
Nikolai
N
Kurtzhals
Jørgen A L
JA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000469:parasitology / Q000473:pathology; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013997:Time Factors
D016207:Cytokines; D011994:Recombinant Proteins; D004921:Erythropoietin