ArticleMalaria journal2026
Plasmodium-induced disruption of brain endothelial barrier integrity in vitro and in mice is prevented by inhibitors of farnesyltransferase.
Article in Malaria journal, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundCerebral malaria is a complication of Plasmodium falciparum infections where the integrity of the blood-brain barrier (BBB) is compromised, frequently leading to persistent neurological sequelae or death. The current treatment for cerebral malaria is based on rapid elimination of the parasite with intravenous anti-malarial drugs, but there is no adjunctive treatment that could address the loss of BBB integrity, potentially decreasing sequelae and improving the survival rate. Prenylation, a cellular process that incorporates isoprenoid lipids to specific protein sites, is known to regulate endothelial barrier integrity. Here we have studied the role of the isoprenoid farnesyl pyrophosphate (farnesyl-PP) and of different inhibitors of the enzymes that perform prenylation in endothelial cells to determine their effect on the endothelial barrier disruption induced by Plasmodium falciparum.
methodsAn in vitro model using human brain microvascular endothelial cells (HBMECs) incubated with lysates of P. falciparum-infected red blood cells (iRBCs) and a mouse model of cerebral malaria were used to study the role of the two main prenylation enzymes, farnesyltransferase and geranylgeranyltransferase, in the regulation of endothelial barrier integrity in relation to cerebral malaria.
resultsAddition of exogenous farnesyl-PP to HBMECs incubated with P. falciparum-iRBCs resulted in increased endothelial barrier disruption. Conversely, treatment with inhibitors of farnesyltransferase, but not of geranylgeranyltransferase, resulted in protection of barrier integrity against disruption induced by P. falciparum-iRBCs. Mice infected with Plasmodium berghei that were treated with the farnesyltransferase inhibitor tipifarnib presented delayed onset of cerebral malaria and higher survival rates.
conclusionsInhibitors of farnesyltransferase protect human endothelial cell barrier integrity from disruption induced by P. falciparum in vitro and decrease mortality in mice with experimental cerebral malaria, indicating a role for farnesylation in the regulation of barrier integrity during cerebral malaria and identifying a potential drug target for the protection of the endothelium during severe malaria.
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