We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood-brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation-coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule; however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects. Therefore, trials of pantethine treatment in adjunctive therapy for severe malaria are warranted.blood-brain barrier ͉ phosphatidylserine ͉ Plasmodium ͉ platelet activation L ow-molecular-weight thiols, widely distributed in the living world, show broad physiological activity involving multiple targets. Among them, the dietary provitamin pantethine, a dimer of pantothenic acid linked by disulfide cystamine (1), has been the subject of much research. As a part of CoA, pantethine is a key regulator of lipid metabolism (2-4). Pantethine has been shown also to inhibit in vitro platelet aggregation in a dosedependent manner (5-7), an action that was not clearly understood (5).Because platelets play a central role in the pathological process associated with cerebral malaria (CM), we examined the effects of pantethine administration to mice infected with Plasmodium berghei strain ANKA (PbA). The processes identified by using this model are relevant to the human pathology (8). Susceptible strains of mice infected with PbA develop neurological manifestations rapidly followed by death. The pathology is due not to the direct action of the parasite but to a deleterious immune response of the infected host, involving cerebral vascular inflammation with microcirculatory dysfunction (9-13). The ultimate consequence is disruption of the brain microvasculature, enhancement of blood-brain barrier (BBB) permeability, and edema formation leading to major hemodynamic dysfunction (14-16).One of the earliest steps of the inflamm...

BackgroundThe administration of the ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating ketone body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects.ResultsWe found that dehydrogenase activity and circulating ketone body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH) production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating ketone body levels in MPTP-intoxicated mice, but not in normal animals.ConclusionsThese finding demonstrate the feasibility of the enhancement of endogenous ketone body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders.