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Optimisation pharmacologique des dérivés de la créatine pour le traitement du déficit en transporteur de la créatine

Abstract : Creatine transporter deficiency is a rare brain disease associated with the loss of function of the SLC6A8 (creatine transporter) leading to an absence of creatine at the cerebral level and to a dramatic neurodevelopmental retardation in the children. To date, no effective therapy is available.A potential therapeutic option would be the design of a pharmaceutical formulation of lipophilic prodrugs of creatine that will cross the cell membranes passively and target the neurons in order to restore the creatine content inside these cells.One of the main purposes of this dissertation is to propose an original chemistry synthesis process of creatine esters with long aliphatic chain. These compounds show interesting pharmacological properties of structure-activity relationship between the length of the aliphatic chain (i.e. lipophilicity) and the ability for the drug to enter cerebral endothelial, astroglial and neuronal cells. According to our experimental observations, the dodecyl ester creatine seems to be the best drug candidate. Moreover, the dodecyl ester is acted on by cellular esterases inside patients’ fibroblasts with a functional deficit of the SLC6A8 and increases the intracellular creatine content.The pharmaceutical formulation developed in this study consists by incorporation of dodecyl ester inside a nanovector (Lipid NanoCapsules). Two main advantages can be gained by nanovectorization: firstly, the dodecyl ester is protected from the degradation by plasmatic esterases before reaching the brain. Secondly, the nanovectorization strategy is highly valuable to brain targeting bypassing the blood-brain barrier, which remains until now a major impediment in the drug design for the Central Nervous System. Our experimental observations highlight this two-step therapeutic strategy for the treatment of deficiency of the creatine transporter.This work was financially supported by the International PhD Program of the Life Sciences division of the CEA and the Fondation Jérôme Lejeune.
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Contributor : Abes Star :  Contact
Submitted on : Tuesday, April 2, 2013 - 4:42:11 PM
Last modification on : Monday, December 13, 2021 - 9:15:05 AM
Long-term archiving on: : Wednesday, July 3, 2013 - 4:08:38 AM


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  • HAL Id : tel-00806976, version 1


Alexandra Trotier-Faurion. Optimisation pharmacologique des dérivés de la créatine pour le traitement du déficit en transporteur de la créatine. Sciences agricoles. Université Paris Sud - Paris XI, 2013. Français. ⟨NNT : 2013PA114810⟩. ⟨tel-00806976⟩



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