Background: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum
infection which may result in death or developmental disability. The pathologic processes leading
to CM are not fully elucidated; however, widely accepted mechanisms include parasite sequestration,
release of infected red blood cell contents, activation of endothelial cells, increased inflammatory
responses, and ultimately dysfunction of the neurovascular unit (NVU). The endothelium
plays a central role in these processes as the site of parasitized erythrocyte sequestration and as the
regulator of fluid extravasation into the central nervous system. Modulating endothelial barrier
function at the NVU may provide new therapeutic approaches to improve outcomes in CM.
Methods: Here we provide a narrative review of the literature of peer-reviewed research relating
to adjunctive therapies for CM. We discuss regulatory pathways of the NVU, with a focus on the
potential for pharmacologic modulation of the NVU to improve CM outcomes.
Results: Recently licensed pharmaceuticals, developed as therapies for cancer or neurologic
disease, could be re-purposed for use as host-directed therapies in CM to target pathways involved
in endothelial stability and activation.
Conclusion: The findings of this review highlight recently licensed pharmaceuticals that may be
developed as future adjunctive therapies for CM.