Protective effects of artesunate on the neurovascular unit by regulating PDGFRβ signaling in experimental cerebral malaria

Cerebral malaria (CM) is a severe manifestation of malaria that significantly impacts the central nervous system, and current therapeutic options are inadequate in addressing the associated neurovascular damage. This study aimed to investigate the protective effects of artesunate on the neurovascular unit (NVU) in experimental cerebral malaria (ECM) by elucidating the underlying molecular mechanisms and signaling pathways involved. It demonstrated artesunate significantly reduced parasitemia and improved behavioral and physiological manifestations, and protected the NVU by increasing NeuN-positive neurons and αII-Spectrin and Connexin 43 (CX43) mRNA levels, while decreasing vascular endothelial growth factor α (VEGFα) mRNA and S100β levels. It also reduced astrocyte and microglia activation, mitigating neuroinflammation. Furthermore, our study indicates that platelet-derived growth factor receptor β (PDGFRβ) is crucial in the NVU protection conferred by artesunate. By using a PDGFRβ pharmacological inhibitor, NVU protective effects of artesunate during the severe episode of ECM were weakened, as evaluated by reduced NeuN-positive neurons and lower levels of Claudin5, zonula occludens-1 (ZO-1), CX43, and Synaptophysin. In addition, artesunate enhanced PDGFRβ protein and suppressed phosphatidylinositol 3-kinase (PI3K)/threonine kinase (Akt) pathway, which was elevated in ECM. The addition of a PDGFRβ Inhibitor increased PI3K/Akt signaling, suggesting the potential mechanism of artesunate to exert its protective effects on the NVU through the PDGFRβ and PI3K/Akt pathway in ECM. These results suggest that artesunate not only acts as an antimalarial agent but also have therapeutic potential in protecting the NVU through host proteins in cerebral malaria. This study lays groundwork for future research exploring new therapeutic strategies for malaria based on host proteins and signaling pathways.

Artesunate; Experimental cerebral malaria; Neurovascular unit; PDGFRβ.