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.