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.