Nilotinib attenuates vascular pathology in experimental cerebral malaria

Cerebral malaria (CM), a life-threatening complication of Plasmodium falciparum infection, is characterized by the sequestration of infected erythrocytes in the brain microvasculature. Our study investigated the potential of repurposing anti-cancer BCR-ABL drugs, also known to be effective against P. falciparum blood-stage parasites, for mitigating inflammation and blood-brain barrier breakdown in CM. Our analysis demonstrated differential protective effects of BCR-ABL drugs on primary human brain microvascular endothelial cells (HBMEC) exposed to thrombin or P. falciparum-infected erythrocyte (IE) challenge. Bosutinib attenuated both thrombin and parasite-induced barrier alterations, while nilotinib was only effective against thrombin, and imatinib protected against neither. Bosutinib's barrier protective effect was associated with reduced interendothelial gap formation and decreased phosphorylation of the adherens junction protein VE-cadherin and the focal adhesion protein paxillin. In the mouse experimental cerebral malaria (ECM) model, nilotinib showed superior efficacy compared to imatinib and bosutinib. In mice, nilotinib resulted in lower brain hemorrhages and vascular congestion compared to anti-malaria drug artesunate at similar levels of parasitemia control. Our findings provide important mechanistic insight into the activities of BCR-ABL drugs to suppress endothelial barrier disruptive signaling in vitro and protect in a mouse model of CM. These findings can inform the repurposing of these drugs in malaria treatment, particularly for managing cerebral complications.