ABSTRACT
We recently raised concern over using hydroxyurea (HU) in the treatment of sickle cell disease in areas endemic for malaria, becauseit up-regulates the endothelial surface expression of ICAM-1, a major receptor for Plasmodium falciparum-infected erythrocytes in the brain. Using human in vitro models of cerebral malaria, we evaluated the interaction of HU with parasites and demonstrated that HU pretreatment increased the number of infected red blood cells adhering to the endothelium, but did not increase endothelial apoptosis. Moreover, using an experimental cerebral malaria model, HU pretreatment was found to prevent significantly mice from developing neurological syndrome by inhibiting parasite growth, opening potential therapeutic avenues.
Subject(s)
Antisickling Agents/administration & dosage , Antisickling Agents/therapeutic use , Cell Adhesion/drug effects , Hydroxyurea/pharmacology , Hydroxyurea/therapeutic use , Malaria, Cerebral/drug therapy , Malaria, Falciparum/drug therapy , Plasmodium falciparum/growth & development , Anemia, Sickle Cell/drug therapy , Animals , Antisickling Agents/pharmacology , Apoptosis , Endothelial Cells/drug effects , Endothelial Cells/physiology , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Erythrocytes/metabolism , Erythrocytes/parasitology , Humans , Hydroxyurea/administration & dosage , Intercellular Adhesion Molecule-1/metabolism , Malaria, Cerebral/mortality , Malaria, Cerebral/parasitology , Malaria, Falciparum/mortality , Malaria, Falciparum/parasitology , Mice , Mice, Inbred C57BL , Plasmodium falciparum/drug effects , Plasmodium falciparum/physiology , Treatment OutcomeABSTRACT
Malaria and human African trypanosomiasis represent the two major tropical vector-transmitted protozoan infections, displaying different prevalence and epidemiological patterns. Death occurs mainly due to neurological complications which are initiated at the blood-brain barrier level. Adapted host-immune responses present differences but also similarities in blood-brain barrier/parasite interactions for these diseases: these are the focus of this review. We describe and compare parasite evasion mechanisms, the initiating mechanisms of central nervous system pathology and major clinical and neuropathological features. Finally, we highlight the common immune mediated mechanisms leading to brain involvement. In both diseases neurological damage is caused mainly by cytokines (interferon-gamma, tumour necrosis factor-alpha and IL-10), nitric oxide and endothelial cell apoptosis. Such a comparative analysis is expected to be useful in the comprehension of disease mechanisms, which may in turn have implications for treatment strategies.
