The development of new drugs is one of the strategies to control
malaria.
Isoprenoid biosynthesis in Plasmodium falciparum is an essential pathway for parasite survival, and is therefore a potential target for new
antimalarial drugs. Indeed, plant-derived secondary metabolites, such as
terpenes, exhibit
antimalarial activity in vitro by inhibiting
isoprenoid biosynthesis in P. falciparum. In this study, the in vitro antiplasmodial activity of
perillyl alcohol (POH) was evaluated, along with its in vitro toxicity and its effect on the isoprenylation process. In addition, the efficacy of intranasally administered POH in preventing Plasmodium berghei ANKA-induced experimental
cerebral malaria (ECM) was determined. The 50% inhibitory concentrations of POH for 3D7 and K1 P. falciparum were 4.8 µM and 10.4 µM, respectively. POH inhibited farnesylation of 20-37 kDa
proteins in P. falciparum (3D7), but no toxic effects in Vero cells were observed. A 500 mg/kg/d dose of POH had no effect on P. berghei ANKA parasitaemia, but showed marked efficacy in preventing ECM development (70% survival compared with 30% for untreated animals). This effect was associated with the downregulation of cerebrovascular
inflammation and damage, with marked decreases in brain leucocyte accumulation and the incidence of brain microhaemorrhage. POH also downregulated
interleukin (IL)-10,
IL-6, tumour
necrosis factor-α,
interferon-γ,
IL-12 and
monocyte chemoattractant protein-1 levels in the brain and spleen. In conclusion, POH shows antiplasmodial activity in vitro and, despite there being no evidence of antiplasmodial activity in vivo following
intranasal administration, POH prevented cerebrovascular
inflammation/damage and expression of pro-inflammatory
cytokines.