Potential cerebral malaria therapy: intramuscular arteether and vitamin D co-administration

Cerebral malaria (CM) shows lethality rate of 15-25% despite effective antimalarial chemotherapy. The effective adjunct treatment to counteract the CM pathogenesis is urgently required. In murine CM model, most interventions studied till date are administered before the onset of CM symptoms, which belittle its translational value to human. We studied intramuscular arteether-vitamin D (ART-VD) combination treatment for CM outcome improvement after the onset of neurological symptoms. The intramuscular dose of 50 µg kg-1 VD for 3 days combined with a loading dose of 25 mg kg-1 α/β arteether followed by 12·5 mg kg-1 dose for two consecutive days led to significant improvement in survival (73% in combination group vs 29 and 0% in arteether and VD monotherapy, respectively) and clinical recovery. The treatment in all the groups partially restored the blood-brain barrier integrity and reduced the level of serum proinflammatory cytokines tumour necrosis factor-α and interferon-γ. The brain transcripts of inflammatory chemokines viz. CXCL10, CXCL9, CCL4 and CCL5 and T cell migration in the brain microvasculature were significantly diminished in all the treatment groups. ART-VD treatment significantly reduced intercellular cell adhesion molecule-1 expression. Taken together, our findings show that coordinated actions of ART-VD improve the outcome of experimental CM.