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

Lothar Wiese; Casper Hempel; Milena Penkowa; Nikolai Kirkby; Jørgen A L Kurtzhals

doi:10.1186/1475-2875-7-3

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

Lothar Wiese, Casper Hempel, Milena Penkowa, Nikolai Kirkby, Jørgen A L Kurtzhals

Afdeling for Klinisk Mikrobiologi

67 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Malaria Journal
Vol/bind	7
Sider (fra-til)	3
ISSN	1475-2875
DOI	https://doi.org/10.1186/1475-2875-7-3
Status	Udgivet - 7 jan. 2008

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10.1186/1475-2875-7-3

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@article{7b43322f90c647698eed9a6edb822d34,

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

abstract = "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.",

keywords = "Animals, Apoptosis/drug effects, Brain/metabolism, Cytokines/genetics, Disease Models, Animal, Dose-Response Relationship, Drug, Erythropoietin/administration & dosage, Female, Gene Expression Regulation/drug effects, Humans, In Situ Nick-End Labeling, Injections, Intraperitoneal, Malaria, Cerebral/drug therapy, Mice, Mice, Inbred C57BL, Neurons/drug effects, Plasmodium berghei/drug effects, Recombinant Proteins, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Time Factors",

author = "Lothar Wiese and Casper Hempel and Milena Penkowa and Nikolai Kirkby and Kurtzhals, {J{\o}rgen A L}",

year = "2008",

month = jan,

day = "7",

doi = "10.1186/1475-2875-7-3",

language = "English",

volume = "7",

pages = "3",

journal = "Malaria Journal",

issn = "1475-2875",

publisher = "BioMed Central Ltd",

}

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

PY - 2008/1/7

Y1 - 2008/1/7

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.

KW - Animals

KW - Apoptosis/drug effects

KW - Brain/metabolism

KW - Cytokines/genetics

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Erythropoietin/administration & dosage

KW - Female

KW - Gene Expression Regulation/drug effects

KW - Humans

KW - In Situ Nick-End Labeling

KW - Injections, Intraperitoneal

KW - Malaria, Cerebral/drug therapy

KW - Mice

KW - Mice, Inbred C57BL

KW - Neurons/drug effects

KW - Plasmodium berghei/drug effects

KW - Recombinant Proteins

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Survival Rate

KW - Time Factors

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 -

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

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