Repurposing Pharmaceuticals as Neuroprotective Agents for Cerebral Malaria

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.