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 antiapoptotic 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.