Protection against cerebral malaria by the low-molecular-weight thiol pantethine.
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.
Penet
Marie-France
MF
Centre de Résonance Magnétique Biologique et Médicale, Unite Mixte de Recherche Centre National de la Recherche Scientifique 6612, Université de la Méditerranée, 13005 Marseille, France.
Abou-Hamdan
Mhamad
M
Coltel
Nicolas
N
Cornille
Emilie
E
Grau
Georges E
GE
de Reggi
Max
M
Gharib
Bouchra
B
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008808:Mice, Inbred CBA; D008970:Molecular Weight; D010204:Pantetheine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010539:Permeability / Q000187:drug effects; D010962:Plasmodium berghei; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D013577:Syndrome
D010975:Platelet Aggregation Inhibitors; D010204:Pantetheine; C005425:pantethine