Protective and reversal actions of a novel peptidomimetic against a pivotal toxin implicated in Alzheimer’s disease - 09/12/18
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Graphical abstract |
Highlights |
• | Real-time optical imaging of ex vivo brain slices enables the direct visualisation of the reversal of noxious effects exerted by T30 toxic peptide. |
• | The peptide T30 has a dose-dependent acute effect on neuronal group activity in the rat basal forebrain. |
• | The cyclised active sequence of T30 (NBP14) and a peptidomimetic (NB-0193) block excessive cellular calcium entry through the α7-nAChR. |
• | The pharmacokinetic features of NB-0193 suggest it could be a promising candidate for a new therapeutic approach for Alzheimer’s disease. |
Abstract |
Despite the many attempts to understand the aetiology of Alzheimer’s disease, the basic mechanisms accounting for the progressive cycle of neuronal loss are still unknown. Previous work has suggested that the pivotal molecule mediating neurodegeneration could be an independently acting peptide cleaved from acetylcholinesterase. This previously unidentified agent acts as a signalling molecule in selectively vulnerable groups of cells where erstwhile developmental mechanisms are activated inappropriately to have a toxic effect in the context of the mature brain. We have previously shown that the toxic actions of this peptide, whose level is doubled in the Alzheimer brain, can be blocked by a cyclised variant (NBP14). However, the size and properties of NBP14 would render it unlikely as a feasible therapeutic candidate. Here therefore we test a synthetic peptidomimetic (NB-0193), modelled on the binding of NBP14 to the target alpha-7 nicotinic receptor, and benchmarked against it to screen for reversal effects using real-time optical imaging in rat brain slices. The blocking action of NB-0193 was confirmed by testing its effect against peptide-induced calcium influx in cell cultures, where it showed a dose-dependent profile over a trophic-toxic range. Moreover, NB-0193 presented promising pharmacokinetic characteristics and could therefore prompt a new therapeutic approach against Alzheimer’s disease.
Le texte complet de cet article est disponible en PDF.Keywords : Acetylcholinesterase, Alzheimer's disease, α7 nicotinic receptor, Peptidomimetic, Voltage-sensitive dye imaging, Ex vivo
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Vol 109
P. 1052-1061 - janvier 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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