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A new therapeutic strategy to manage excitotoxicity during Alzheimer's disease

Zaghmi, Ahlem; Greschner, Andrea; Ramassamy, Charles; Gauthier, Marc A. . A new therapeutic strategy to manage excitotoxicity during Alzheimer's disease In: 12ème colloque du centre de recherche Biomed, 5 mai 2016, Centre de congrès Palace, Laval (Québec).

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Résumé

Glutamate, as the major excitatory neurotransmitter in the central nervous system, is involved in many aspects of normal brain function including learning, memory and behavior (Campos - Peña et al. , 2014, Hynd et al. , 2004). During Alzheimer’s disease (AD), the high levels of glutamate, induces excitotoxicity and leads to neuronal death and loss of cognitive function. Some studies have suggested that reducing blood levels of glutamate could induce efflux from the brain to the blood thereof leading to the decrease in the cerebral concentrations (Boyko et al. , 2014, Ruban et al. , 2014).

Our hypothesis is that the use of enzyme - polymer bio - conjugates could be interesting for the treatment of AD. The glutamate dehydrogenase (GDH) via its catalytic activity, will consume the excess glutamate and the biocompatible polymer selected, which is polyethylene glycol (PEG), will increase the duration of circulatory half - life.

We propose, therefore, to synthesize conjugates GDH - PEG, to validate the mainte- nance of enzymatic activity and check their therapeutic efficacy. For this purpose, we conjugate PEG on the surface of the GDH (by using 2 ratios), we validate the reaction by visualization of our bio conjugates by SDS PAGE and by separating them with Size exclusion chromatography. After that we characterize the number of PEG per GDH by NMR and we evaluate the enzymatic activity before and after bio - conjugation.

Our results demonstrate that the use of different Ratio allows us to have variable number of PEG grafted on the surface of our enzyme. After PEGylation, we showed that the enzyme activity is maintained. Currently, we are planning tests in vitro and in vivo in streptozotocine rat’s models, well known animal model for sporadic AD, to evaluate the effectiveness of the elimination of the excess toxic glutamate from the cerebrospinal fluid.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Présentation par affiche
Mots-clés libres: -
Centre: Centre Énergie Matériaux Télécommunications
Centre INRS-Institut Armand Frappier
Date de dépôt: 25 déc. 2017 22:14
Dernière modification: 25 déc. 2017 22:14
URI: http://espace.inrs.ca/id/eprint/6618

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