Nilotinib attenuates vascular pathology in experimental cerebral malaria
Abstract: 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 tyrosine kinase inhibitors targeting BCR-ABL1 (BCR-AB...
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| Format: | Article |
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Elsevier
2025-05-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952925001296 |
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| author | Luana S. Ortolan Priyanka Bansal Veronica I. Primavera Rodrigo J. R. X. Freitas Ling Wei Sabrina Epiphanio Alexis Kaushansky Joseph D. Smith |
| author_facet | Luana S. Ortolan Priyanka Bansal Veronica I. Primavera Rodrigo J. R. X. Freitas Ling Wei Sabrina Epiphanio Alexis Kaushansky Joseph D. Smith |
| author_sort | Luana S. Ortolan |
| collection | DOAJ |
| description | Abstract: 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 tyrosine kinase inhibitors targeting BCR-ABL1 (BCR-ABL drugs), which are 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 exposed to thrombin or a P falciparum-infected erythrocyte challenge. Bosutinib attenuated both thrombin- and parasite-induced barrier alterations, whereas 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 CM model, nilotinib showed superior efficacy over imatinib and bosutinib. In mice, nilotinib led to fewer brain hemorrhages and less vascular congestion than the antimalaria 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 to protect in a mouse model of CM. These findings can inform the repurposing of these drugs in malaria treatment, particularly for managing cerebral complications. |
| format | Article |
| id | doaj-art-2267f02f564c4314a94fb2f2e089c1ed |
| institution | DOAJ |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-2267f02f564c4314a94fb2f2e089c1ed2025-08-20T03:09:44ZengElsevierBlood Advances2473-95292025-05-019102473248810.1182/bloodadvances.2024015364Nilotinib attenuates vascular pathology in experimental cerebral malariaLuana S. Ortolan0Priyanka Bansal1Veronica I. Primavera2Rodrigo J. R. X. Freitas3Ling Wei4Sabrina Epiphanio5Alexis Kaushansky6Joseph D. Smith7Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WACenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WACenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WADepartment of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, BrazilCenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WADepartment of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, BrazilCenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA; Department of Pediatrics, University of Washington, Seattle, WACenter for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA; Department of Pediatrics, University of Washington, Seattle, WA; Correspondence: Joseph D. Smith, Center for Global Infectious Disease Research, Seattle Children’s Research Institute, 1916 Boren Ave, Seattle, WA 98101;Abstract: 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 tyrosine kinase inhibitors targeting BCR-ABL1 (BCR-ABL drugs), which are 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 exposed to thrombin or a P falciparum-infected erythrocyte challenge. Bosutinib attenuated both thrombin- and parasite-induced barrier alterations, whereas 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 CM model, nilotinib showed superior efficacy over imatinib and bosutinib. In mice, nilotinib led to fewer brain hemorrhages and less vascular congestion than the antimalaria 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 to protect in a mouse model of CM. These findings can inform the repurposing of these drugs in malaria treatment, particularly for managing cerebral complications.http://www.sciencedirect.com/science/article/pii/S2473952925001296 |
| spellingShingle | Luana S. Ortolan Priyanka Bansal Veronica I. Primavera Rodrigo J. R. X. Freitas Ling Wei Sabrina Epiphanio Alexis Kaushansky Joseph D. Smith Nilotinib attenuates vascular pathology in experimental cerebral malaria Blood Advances |
| title | Nilotinib attenuates vascular pathology in experimental cerebral malaria |
| title_full | Nilotinib attenuates vascular pathology in experimental cerebral malaria |
| title_fullStr | Nilotinib attenuates vascular pathology in experimental cerebral malaria |
| title_full_unstemmed | Nilotinib attenuates vascular pathology in experimental cerebral malaria |
| title_short | Nilotinib attenuates vascular pathology in experimental cerebral malaria |
| title_sort | nilotinib attenuates vascular pathology in experimental cerebral malaria |
| url | http://www.sciencedirect.com/science/article/pii/S2473952925001296 |
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