Synergistic Effect of Combined Artesunate and Tetramethylpyrazine in Experimental Cerebral Malaria

Intravenous artesunate is effective against cerebral malaria (CM), but high mortality and neurological sequelae in survivors are inevitable. We investigated the effect of combined artesunate and tetramethylpyrazine using mouse models of experimental cerebral malaria (ECM). Artesunate + tetramethylpyrazine reduced microvascular blockage and improved neurological function, including the rapid murine coma and behavior scale (RMCBS), leading to improved survival and reduced pathology in ECM. This combination downregulated the expression of adhesion molecules and sequestration of parasitized red blood cells (pRBCs), increased cerebral blood flow, nerve growth factor (b-NGF), vascular endothelial growth factor A (VEGF-A), and neurotrophin (brain-derived neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3)) levels, and alleviated hippocampal neuronal damage and astrocyte activation. Down- (n = 128) and upregulated (n = 64) proteins were identified in the artesunate group, while up- (n = 217) and downregulated (n = 177) proteins were identified in the artesunate + tetramethylpyrazine group, presenting a significantly altered proteome profile. KEGG analysis showed that 166 differentially expressed proteins were enriched in the Art group and 234, in the artesunate + tetramethylpyrazine group. The neuroprotective effects of artesunate + tetramethylpyrazine were mainly related to proteins involved in axon development and transportation between blood and brain. These results suggested that artesunate + tetramethylpyrazine could be a potential adjuvant therapy against CM, but this will have to be confirmed in future studies and trials.