Excitotoxicity-induced endocytosis confers drug targeting in cerebral ischemia.

Détails

ID Serval
serval:BIB_C58331D4DEC7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Excitotoxicity-induced endocytosis confers drug targeting in cerebral ischemia.
Périodique
Annals of Neurology
Auteur(s)
Vaslin A., Puyal J., Clarke P.G.H.
ISSN
1531-8249[electronic], 0364-5134[linking]
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
65
Numéro
3
Pages
337-347
Langue
anglais
Résumé
OBJECTIVE: Targeting neuroprotectants specifically to the cells that need them is a major goal in biomedical research. Many peptidic protectants contain an active sequence linked to a carrier such as the transactivator of transcription (TAT) transduction sequence, and here we test the hypothesis that TAT-linked peptides are selectively endocytosed into neurons stressed by excitotoxicity and focal cerebral ischemia. METHODS: In vivo experiments involved intracerebroventricular injection of TAT peptides or conventional tracers (peroxidase, fluorescein isothiocyanate-dextran) in young rats exposed to occlusion of the middle cerebral artery at postnatal day 12. Cellular mechanisms of uptake were analyzed in dissociated cortical neuronal cultures. RESULTS: In both models, all tracers were taken up selectively into stressed neurons by endocytosis. In the in vivo model, this was neuron specific and limited to the ischemic area, where the neurons displayed enhanced immunolabeling for early endosomal antigen-1 and clathrin. The highly efficient uptake of TAT peptides occurred by the same selective mechanism as for conventional tracers. All tracers were targeted to the nucleus and cytoplasm of neurons that appeared viable, although ultimately destined to die. In dissociated cortical neuronal cultures, an excitotoxic dose of N-methyl-D-aspartate induced a similar endocytosis. It was 100 times more efficient with TAT peptides than with dextran, because the former bound to heparan sulfate proteoglycans at the cell surface, but it depended on dynamin and clathrin in both cases. INTERPRETATION: Excitotoxicity-induced endocytosis is the main entry route for protective TAT peptides and targets selectively the neurons that need to be protected.
Mots-clé
Alanine/genetics, Animals, Animals, Newborn, Brain Ischemia/drug therapy, Cells, Cultured, Cerebral Cortex/cytology, Dextrans/diagnostic use, Dextrans/metabolism, Disease Models, Animal, Dynamin I/genetics, Endocytosis/drug effects, Excitatory Amino Acid Agonists/toxicity, Fluorescein-5-isothiocyanate/analogs &amp, derivatives, Fluorescein-5-isothiocyanate/diagnostic use, Gene Products, tat/metabolism, Green Fluorescent Proteins/genetics, Horseradish Peroxidase/diagnostic use, Horseradish Peroxidase/metabolism, Injections, Intraventricular/methods, Lysine/genetics, Male, Mutation/genetics, N-Methylaspartate/toxicity, Neurons/drug effects, Neurons/physiology, Rats, Rats, Sprague-Dawley, Transfection/methods, Vesicular Transport Proteins/metabolism
Pubmed
Web of science
Création de la notice
27/04/2009 11:25
Dernière modification de la notice
20/08/2019 16:41
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