Key result
Adjunctive therapy with the AT1 blocker irbesartan or the AT2 agonist compound 21 significantly increased survival from experimental cerebral malaria in mice compared to chloroquine alone (65% and 73% vs 18%, respectively, P<0.01).
Absolute Event Rate: 65% vs 18%
p-value: p=<0.01
Targeting angiotensin II receptors preserves brain endothelial integrity and improves survival in preclinical models of cerebral malaria.
Cautions against clinical use of irbesartan or compound 21 in cerebral malaria; leaves open angiotensin receptor targeting for future translational studies.
Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum-infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter-endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin-induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC-induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.
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Gallego‐Delgado et al. (2016) studied Experimental cerebral malaria (n=54). Irbesartan or Compound 21 (Angiotensin II receptor modulators) vs. Chloroquine alone was evaluated on Total survival (p=<0.01). Adjunctive therapy with the AT1 blocker irbesartan or the AT2 agonist compound 21 significantly increased survival from experimental cerebral malaria in mice compared to chloroquine alone (65% and 73% vs 18%, respectively, P<0.01).
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