Donecopride, a Swiss army knife with potential against Alzheimer's disease
Open Access
- 27 December 2019
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 177 (9), 1988-2005
- https://doi.org/10.1111/bph.14964
Abstract
Background and Purpose We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5âHT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD). Experimental Approach We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloidâÎČ peptides and, in vitro, primary cultures of rat hippocampal neurons. Proâcognitive and antiâamnesic effects were evaluated with novel object recognition, Yâmaze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloidâÎČ peptides on neuronal survival and neurite formation determined in vitro. Key Results In vivo, chronic (3 months) administration of donecopride displayed potent antiâamnesic properties in the two mouse models of AD, preserving learning capacities, including working and longâterm spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloidâÎČ peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses. Conclusions and Implications Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential diseaseâmodifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.Funding Information
- Fondation Vaincre Alzheimer (12721)
- Agence Nationale de la Recherche (ANRâ12âBSV4â008â01, ANRâ15âCE16â0006, ANRâ12âJS007â0012â01)
This publication has 69 references indexed in Scilit:
- Area-Specific Alterations of Synaptic Plasticity in the 5XFAD Mouse Model of Alzheimerâs Disease: Dissociation between Somatosensory Cortex and HippocampusPLOS ONE, 2013
- N-truncated amyloid ÎČ (AÎČ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficitsActa Neuropathologica, 2013
- Operational dissection of ÎČâamyloid cytopathic effects on cultured neuronsJournal of Neuroscience Research, 2013
- What pharmacological interventions indicate concerning the role of the perirhinal cortex in recognition memoryNeuropsychologia, 2012
- Executive deficits are related to the inferior frontal junction in early dementiaBrain, 2011
- Detecting cognitive impairment by eye movement analysis using automatic classification algorithmsJournal of Neuroscience Methods, 2011
- Animal research: Reporting in vivo experiments: The ARRIVE guidelinesBritish Journal of Pharmacology, 2010
- Prefrontal cortex and hippocampus subserve different components of working memory in ratsLearning & Memory, 2008
- Clinical course of neuropathologically confirmed frontal-variant Alzheimer's diseaseNature Clinical Practice Neurology, 2008
- Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory testsLearning & Memory, 2006