Protection against cerebral malaria by the low-molecular-weight thiol pantethine
| Autor: | Marie-France Penet, Nicolas Coltel, Max de Reggi, Mhamad Abou-Hamdan, Emilie Cornille, Georges E. Grau, Bouchra Gharib |
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| Přispěvatelé: | Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Unité des Rickettsies et pathogènes émergents (URPE), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Platelet Aggregation
Plasmodium berghei Pharmacology MESH: Blood-Brain Barrier chemistry.chemical_compound Mice 0302 clinical medicine MESH: Animals MESH: Syndrome MESH: Platelet Aggregation Cell Line Transformed 0303 health sciences MESH: Mice Inbred CBA Multidisciplinary MESH: Molecular Weight Pantethine Syndrome Biological Sciences 3. Good health medicine.anatomical_structure Biochemistry MESH: Platelet Aggregation Inhibitors Cerebral Malaria Blood-Brain Barrier MESH: Permeability Pantetheine Platelet aggregation inhibitor [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Female Malaria Cerebral Biology Blood–brain barrier MESH: Pantetheine Permeability Cell Line MESH: Malaria Cerebral 03 medical and health sciences Cystamine medicine MESH: Plasmodium berghei Animals Humans MESH: Cell Line Transformed Platelet activation MESH: Mice 030304 developmental biology MESH: Humans biology.organism_classification MESH: Cell Line Molecular Weight chemistry Mice Inbred CBA MESH: Female 030217 neurology & neurosurgery Platelet Aggregation Inhibitors |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2008, 105 (4), pp.1321-6. ⟨10.1073/pnas.0706867105⟩ Proceedings of the National Academy of Sciences of the United States of America, 2008, 105 (4), pp.1321-6. ⟨10.1073/pnas.0706867105⟩ |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.0706867105⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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