Abstract
BackgroundCerebral 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.MethodsA 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.ResultsCDDO-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.ConclusionsThese 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.
Highlights
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection associated with high mortality and neurocognitive impairment in survivors
Mice were assessed for signs of experimental model of cerebral malaria (ECM) using a modified rapid murine coma and behaviour scale (RMCBS) [36] and were euthanized when moribund according to institutional guidelines [37]
Mono‐ and adjunctive CDDO‐ethyl amide (EA) therapy improves outcome in experimental cerebral malaria To determine whether therapeutic administration of CDDO-ethyl amide (CDDO-EA) would improve outcome in C57BL/6J mice susceptible to ECM, Plasmodium berghei ANKA (PbA)-infected mice were either treated with a single dose of CDDO-EA alone or in combination with artesunate
Summary
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection associated with high mortality and neurocognitive impairment in survivors. Current elimination efforts have considerably reduced the global malaria burden, these advances may paradoxically increase the risk of severe and fatal disease as the level of clinical immunity in the population wanes due to decreased parasite prevalence [3, 4]. The mechanisms underlying cerebral malaria (CM) are incompletely understood, an interaction between both parasite virulence factors and host response determinants play critical roles in the pathobiology of CM. C57BL/6 mice infected with Plasmodium berghei strain ANKA serves as an experimental model of cerebral malaria (ECM), where mice develop severe vasculopathy and neurological manifestations [5, 9,10,11,12,13]. While some features differ between ECM and human CM, those involving microvascular leakage
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