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Background  Cerebral malaria (CM) is a severe complication of  Plasmodium falciparum  infection associated with high mortality and neurocognitive impairment in survivors. New anti-malarials and host-based adjunctive therapy may improve clinical outcome in CM. Synthetic oleanane triterpenoid (SO) compounds have shown efficacy in the treatment of diseases where inflammation and oxidative stress contribute to pathogenesis.    Methods  A derivative of the SO 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), CDDO-ethyl amide (CDDO-EA) was investigated for the treatment of severe malaria in a pre-clinical model. CDDO-EA was evaluated in vivo as a monotherapy as well as adjunctive therapy with parenteral artesunate in the  Plasmodium berghei  strain ANKA experimental cerebral malaria (ECM) model.    Results  CDDO-EA alone improved outcome in ECM and, given as adjunctive therapy in combination with artesunate, it significantly improved outcome over artesunate alone (p = 0.009). Improved survival was associated with reduced inflammation, enhanced endothelial stability and blood–brain barrier integrity. Survival was improved even when administered late in the disease course after the onset of neurological symptoms.    Conclusions  These results indicate that SO are a new class of immunomodulatory drugs and support further studies investigating this class of agents as potential adjunctive therapy for severe malaria.

Synthetic oleanane triterpenoids enhance blood brain barrier integrity and improve survival in experimental cerebral malaria