Probucol dramatically enhances dihydroartemisinin effect in murine malaria

Area of Science:

• Malariology
• Pharmacology
• Oxidative Stress Research

Background:

• Artemisinin-based combination therapy (ACT) is a frontline malaria treatment.
• Emerging artemisinin resistance and slow parasite clearance necessitate new therapeutic strategies.
• Dihydroartemisinin (DHA) resistance risk increases as parasites are exposed to partner drugs alone.

Purpose of the Study:

• To investigate the potential of probucol as a combination drug to enhance the efficacy of DHA against malaria.
• To explore the mechanisms underlying probucol's effect on malaria infection.

Main Methods:

• Plasmodium yoelii XL-17 infected C57BL/6J mice were treated with probucol and/or DHA.
• Probucol was administered via a mixed diet, while DHA was injected daily.
• Mechanisms were investigated by measuring 8-OHdG (oxidized DNA biomarker) in infected red blood cells and assessing vitamin E levels.

Main Results:

• Both probucol and DHA dose-dependently reduced parasitemia and increased survival rates.
• Probucol treatment significantly increased 8-OHdG levels in infected red blood cells.
• Vitamin E supplementation negated probucol's antimalarial effect and its impact on plasma vitamin E.

Conclusions:

• Probucol enhances antimalarial effects through oxidative stress induction, potentially via vitamin E deficiency.
• Prophylactic probucol treatment reduces the effective dose of DHA for malaria.
• Probucol is a potential candidate for prophylactic use to potentiate DHA therapy.