Cerebral malaria (CM), caused by Plasmodium falciparum, is the primary cause of death from severe malaria. Even after immediate parenteral therapy with antimalarial drugs, the mortality rate remains 15 to 25%. Currently, no effective therapeutic agents are available for the radical treatment of CM. Thus, further in-depth explorations of adjuvant therapies in combination with antimalarial drugs are urgently needed. The experimental cerebral malaria (ECM) model was established by infecting C57BL/6 mice with Plasmodium berghei ANKA. Subsequently, infected mice were continuously treated with dihydroartemisinin (DHA) in combination with rapamycin (RAP) and atorvastatin (AVA) for 5 days at different time points, including day 0, day 3, and day 6 postinfection (p.i.). Treatment efficacy was evaluated by comparing behavioral scores, body weight, parasitemia, survival rate, blood-brain barrier (BBB) integrity, and histopathology. The optimal combination therapy of DHA, RAP, and AVA on day 3 p.i. was selected for ECM. This strategy significantly improved survival rate, reduced parasitemia, improved the rapid murine coma and behavioral scale scores and permeability of the BBB, attenuated cerebrovascular and hepatic central venous obstruction and hemozoin deposition in the liver, and decreased the red pulp area of the spleen, which effectively ameliorated neurological damage in ECM. It also improved histopathology and neurological damage caused by ECM. In this study, the optimal therapeutic strategy for ECM was selected, which is expected to be a potential therapy for human CM. IMPORTANCE Although artemisinin-based combination therapies (ACTs) have greatly improved the clinical outcome of cerebral malaria (CM) as a fatal disease that can permanently disable a significant proportion of children even if they survive, new treatment options are needed as Plasmodium falciparum develops resistance to antimalarial drugs. Recent reports suggest that basal treatment with artemisinin derivatives often fails to protect against cell death, neurological damage, and cognitive deficits. In this study, the combination of dihydroartemisinin with rapamycin and atorvastatin improved the current antimalarial outcomes by overcoming the limitations of current antimalarials for CM morbidity and neurological sequelae. This combination offers a new adjunctive treatment for the clinical treatment of human CM in susceptible populations, including children under 5 years old and pregnant women.
Keywords: Additive therapy; atorvastatin; cerebral malaria; combination therapy; dihydroartemisinin; rapamycin.