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Cerebral malaria (CM) is a severe neurological syndrome in humans and the main fatal cause of malaria. In malaria epidemic regions, despite appropriate anti-malarial treatment, 10–20% of deaths still occur during the acute phase. This is largely attributable to poor treatment access, therapeutic complexity and drug resistance; thus, developing additional clinical adjunctive therapies is an urgent necessity. In this study, we investigated the effect of artesunate (AST) and recombinant human erythropoietin (rhEPO) using an experimental cerebral malaria (ECM) model—C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). Treatment with the combination of AST and rhEPO reduced endothelial activation and improved the integrity of blood brain barrier, which led to increased survival rate and reduced pathology in the ECM. In addition, this combination treatment down-regulated the Th1 response during PbA infection, which was correlated with the reduction of CCL2, TNF-α, IFN-γ, IL-12, IL-18, CXCL9 and CXCL10 levels, leading to reduced accumulation of pathogenic T cells in the brain. Meanwhile, AST and rhEPO combination led to decreased maturation and activation of splenic dendritic cells, expansion of regulatory T cells, and increased IL-10 and TGF-β production. In conclusion, these data provide a theoretical basis for clinical adjunct therapy with rhEPO and AST in human cerebral malaria patients.Erythropoitin-artesunate combination synergistically inhibits Th1 response in ECM.EPO-AST combination blocks DC maturation and function and boosts Treg expansion.EPO-AST combination reduces production of proinflammatory cytokines in splenocytes.EPO-AST combination increases production of anti-inflammatory cytokines.EPO-AST combination improves mouse survival rate and reduces brain pathology.