Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria

TY - JOUR

T1 - Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria

AU - Wiese, Lothar

AU - Hempel, Casper

AU - Penkowa, Milena

AU - Kirkby, Nikolai

AU - Kurtzhals, Jørgen A L

N1 - Keywords: Animals; Apoptosis; Brain; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin, Recombinant; Female; Gene Expression Regulation; Humans; In Situ Nick-End Labeling; Injections, Intraperitoneal; Malaria, Cerebral; Mice; Mice, Inbred C57BL; Neurons; Plasmodium berghei; Reverse Transcriptase Polymerase Chain Reaction; Survival Rate; Time Factors

PY - 2008

Y1 - 2008

N2 - 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. CONCLUSION: These results and its excellent safety profile in humans makes rhEpo a potential candidate for adjunct treatment of CM.

AB - 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. CONCLUSION: These results and its excellent safety profile in humans makes rhEpo a potential candidate for adjunct treatment of CM.

U2 - 10.1186/1475-2875-7-3

DO - 10.1186/1475-2875-7-3

M3 - Journal article

C2 - 18179698

SN - 1475-2875

VL - 7

SP - 3

JO - Malaria Journal

JF - Malaria Journal

ER -