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Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria

Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM is characterized by e...

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Autores principales: Mota, Sabrina, Bensalel, Johanna, Park, Do Hee, Gonzalez, Sandra, Rodriguez, Ana, Gallego-Delgado, Julio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229727/
https://www.ncbi.nlm.nih.gov/pubmed/35745497
http://dx.doi.org/10.3390/pathogens11060643
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author Mota, Sabrina
Bensalel, Johanna
Park, Do Hee
Gonzalez, Sandra
Rodriguez, Ana
Gallego-Delgado, Julio
author_facet Mota, Sabrina
Bensalel, Johanna
Park, Do Hee
Gonzalez, Sandra
Rodriguez, Ana
Gallego-Delgado, Julio
author_sort Mota, Sabrina
collection PubMed
description Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM is characterized by endothelial activation and dysfunction. Several biomarkers of endothelial activation have been associated with CM severity and mortality, making the brain vascular endothelium a potential target for adjunctive therapies. Statins and Angiotensin II Receptor Blockers (ARBs) are drugs used to treat hypercholesterolemia and hypertension, respectively, that have shown endothelial protective activity in other diseases. Here, we used a combination of a statin (atorvastatin) and an ARB (irbesartan) as adjunctive therapy to conventional antimalarial drugs in a mouse experimental model of CM. We observed that administration of atorvastatin–irbesartan combination decreased the levels of biomarkers of endothelial activation, such as the von Willebrand factor and angiopoietin-1. After mice developed neurological signs of CM, treatment with the combination plus conventional antimalarial drugs increased survival rates of animals 3–4 times compared to treatment with antimalarial drugs alone, with animals presenting lower numbers and smaller hemorrhages in the brain. Taken together, our results support the hypothesis that inhibiting endothelial activation would greatly reduce the CM-associated pathology and mortality.
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spelling pubmed-92297272022-06-25 Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria Mota, Sabrina Bensalel, Johanna Park, Do Hee Gonzalez, Sandra Rodriguez, Ana Gallego-Delgado, Julio Pathogens Article Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM is characterized by endothelial activation and dysfunction. Several biomarkers of endothelial activation have been associated with CM severity and mortality, making the brain vascular endothelium a potential target for adjunctive therapies. Statins and Angiotensin II Receptor Blockers (ARBs) are drugs used to treat hypercholesterolemia and hypertension, respectively, that have shown endothelial protective activity in other diseases. Here, we used a combination of a statin (atorvastatin) and an ARB (irbesartan) as adjunctive therapy to conventional antimalarial drugs in a mouse experimental model of CM. We observed that administration of atorvastatin–irbesartan combination decreased the levels of biomarkers of endothelial activation, such as the von Willebrand factor and angiopoietin-1. After mice developed neurological signs of CM, treatment with the combination plus conventional antimalarial drugs increased survival rates of animals 3–4 times compared to treatment with antimalarial drugs alone, with animals presenting lower numbers and smaller hemorrhages in the brain. Taken together, our results support the hypothesis that inhibiting endothelial activation would greatly reduce the CM-associated pathology and mortality. MDPI 2022-06-02 /pmc/articles/PMC9229727/ /pubmed/35745497 http://dx.doi.org/10.3390/pathogens11060643 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mota, Sabrina
Bensalel, Johanna
Park, Do Hee
Gonzalez, Sandra
Rodriguez, Ana
Gallego-Delgado, Julio
Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria
title Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria
title_full Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria
title_fullStr Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria
title_full_unstemmed Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria
title_short Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria
title_sort treatment reducing endothelial activation protects against experimental cerebral malaria
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229727/
https://www.ncbi.nlm.nih.gov/pubmed/35745497
http://dx.doi.org/10.3390/pathogens11060643
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