Evaluation of clinically approved neuroprotective drugs as adjunct therapies in experimental cerebral malaria

Cerebral malaria (CM) remains one of the most severe complications of Plasmodium falciparum infection, often leading to death within days and leaving survivors with lasting cognitive damage. Since current treatments target the parasite but offer little to no neuroprotection, we explored whether existing neuroprotective drugs could help fill this gap. Six clinically-approved drugs, viz. topiramate, rasagiline, vinpocetine, cilostazol, piracetam, and rivastigmine were tested for both antimalarial and anti-cerebral malaria activity. Screening against P. falciparum in vitro showed that vinpocetine, cilostazol, and rivastigmine effectively inhibited parasite growth, without causing toxicity in Vero or BB19 cell lines or in human red blood cells. In a mouse model of experimental CM (Plasmodium berghei ANKA-infected C57BL/6 mice), early oral treatment with cilostazol, piracetam, or rivastigmine delayed the onset of CM symptoms and significantly improved survival compared to untreated controls. When treatment was initiated after the first neurological signs, only the combination of rivastigmine with the fast-acting antimalarial α/β-arteether markedly improved outcomes, including parasite clearance and extended survival, compared to either treatment alone. Overall, these results suggest that combining rivastigmine with α/β-arteether may represent a practical and low-cost adjunct therapy for CM. Further mechanistic and clinical studies will be essential to confirm these findings and assess long-term outcomes.