BACKGROUNDCerebral malaria (CM) is a severe immunovasculopathy caused forPlasmodium falciparuminfection, which is characterised by the sequestration of parasitised red blood cells (pRBCs) in brain microvessels. Previous studies have shown that some terpenes, such as perillyl alcohol (POH), exhibit a marked efficacy in preventing cerebrovascular inflammation, breakdown of the brain-blood barrier (BBB) and brain leucocyte accumulation in experimental CM models.OBJECTIVETo analyse the effects of POH on the endothelium using human brain endothelial cell (HBEC) monolayers co-cultured with pRBCs.METHODOLOGYThe loss of tight junction proteins (TJPs) and features of endothelial activation, such as ICAM-1 and VCAM-1 expression were evaluated by quantitative immunofluorescence. Microvesicle (MV) release by HBEC upon stimulation byP. falciparumwas evaluated by flow cytometry. Finally, the capacity of POH to revertP. falciparum-induced HBEC monolayer permeability was examined by monitoring trans-endothelial electrical resistance (TEER).FINDINGSPOH significantly prevented pRBCs-induced endothelial adhesion molecule (ICAM-1, VCAM-1) upregulation and MV release by HBEC, improved their trans-endothelial resistance, and restored their distribution of TJPs such as VE-cadherin, Occludin, and JAM-A.CONCLUSIONSPOH is a potent monoterpene that is efficient in preventingP. falciparum-pRBCs-induced changes in HBEC, namely their activation, increased permeability and alterations of integrity, all parameters of relevance to CM pathogenesis.