Donecopride, a Swiss army knife with potential against Alzheimer's disease
| Autor: | Kévin Baranger, Patrick Dallemagne, Thomas Freret, Joël Bockaert, Eleazere Cem, Serge Mignani, Michel Boulouard, Katia Hamidouche, Sylvie Claeysen, Patrizia Giannoni, Christophe Rochais, Cédric Lecoutey, Santiago Rivera, Florence Gaven |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Neurite Transgene Morris water navigation task Mice Transgenic Neuroprotection 03 medical and health sciences chemistry.chemical_compound Amyloid beta-Protein Precursor Mice 0302 clinical medicine Piperidines In vivo Alzheimer Disease Medicine Animals Maze Learning Pharmacology Amyloid beta-Peptides Aniline Compounds biology business.industry Brain Acetylcholinesterase Research Papers 3. Good health Rats Disease Models Animal 030104 developmental biology chemistry biology.protein business Neuroscience 030217 neurology & neurosurgery Neurotrophin |
| Zdroj: | Br J Pharmacol |
| Popis: | BACKGROUND AND PURPOSE: We recently identified donecopride as a pleiotropic compound able to inhibit acetylcholinesterase and to activate serotonin subtype 4 receptor. The purpose of the present article is to establish its potential therapeutic interest against Alzheimer's disease (AD). EXPERIMENTAL APPROACH: The present work used both in cellulo and in vivo models of AD. KEY RESULTS: In the present study, we show that, in vivo under chronic administration, donecopride displays potent anti-amnesic properties in two different animal models of Alzheimer's disease (AD) (transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides). Donecopride preserved learning capacities, including working and long-term spatial memories, which were evaluated with various behavioral tests (novel object recognition, Y-maze, Morris water maze). These behavioral observations found molecular correlation with the interactions of donecopride related to the two main types of molecular damage in AD. Indeed, a decrease in amyloid aggregation was observed in the brain of the treated transgenic mice, as well as a reduction in tau hyperphosphorylation in rat primary cultures of hippocampal neurons. At the cellular level, donecopride exerted neuroprotective effects toward neurons and the neurite network, as well as neurotrophic benefits, expressed as the formation of new synapses. CONCLUSIONS & IMPLICATIONS: Pleiotropic donecopride acts like a Swiss army knife, displaying sustainable symptomatic therapeutic effects and potential disease-modifying roles against AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans. |
| Databáze: | OpenAIRE |
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