Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT4 receptor activation (RS67333) on object recognition in mice

Freret, Thomas; Bouët, Valentine; Quiedeville, Anne; Nee, Gérald; Dallemagne, Patrick; Rochais, Christophe; Boulouard, Michel

doi:10.1016/j.bbr.2012.02.012

Cited by 40 publications

(28 citation statements)

References 38 publications

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“…This is surprising given that donepezil is a specific and potent AChE inhibitor, and an increase in ACh availability is the mechanism commonly believed to underlie its procognitive effects. The efficacy of donepezil in ameliorating the performance in the ORT was recently reported in normal rats (Callahan et al, 2013) and mice (Freret et al, 2012), and in cognitively impaired (APP)/presenilin-1 (PS1) transgenic mice (Guo et al, 2015), in the same dose range used in our study. There is conflicting evidence regarding donepezil and GSK-3β.…”

Section: A C C E P T E D Accepted Manuscriptsupporting

confidence: 74%

Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse

et al. 2016

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Section: A C C E P T E D Accepted Manuscriptsupporting

confidence: 74%

Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse

et al. 2016

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“…This effect of RS67333 on the firing of 5-HT neurons is likely to contribute to the phenotype we observe in the current study. Enhanced cognition induced by RS67333 was blocked by the 5-HT 4 receptor antagonist GR 125487 (1 mg/kg, intravenous) (Freret et al, 2012;Lamirault and Simon, 2001). Both studies tested the specificity of the effects of RS67333 in the Novel Object Recognition test by using the highly potent and selective 5-HT 4 receptor antagonist, GR125487.…”

Section: Discussionmentioning

confidence: 99%

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

Mendez‐David

David

Darcet

et al. 2013

Neuropsychopharmacol

142

152

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Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT 4 receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT 4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT 4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety-and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT 4 receptor antagonist (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT 4 receptor activation is necessary for these effects of SSRIs. 5-HT 4 receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.

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“…Interest in such a dual effect has been recently shown with the synergistic coadministration of subactive doses of donepezil and RS67333, which resulted in a significantly procognitive effect (26). Donecopride, which combines the activities of donepezil and RS67333 in a single compound, possesses excellent drugability parameters with a good bioavailability; it also has the ability to cross the BBB and features a nontoxic profile.…”

Section: Discussionmentioning

confidence: 99%

“…These activities seem to be synergistic when they are associated in an AD animal model, which we have recently shown in mice (26). A second pharmacological approach based on the fact that a single compound may be able to hit multiple targets is now emerging.…”

mentioning

confidence: 94%

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Lecoutey

Hédou

Freret

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

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RS67333 is a partial serotonin subtype 4 receptor (5-HT 4 R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitargetdirected ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT 4 R partial agonist (K i = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC 50 = 16 nM) that further promotes sAPPα release (EC 50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

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Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT4 receptor activation (RS67333) on object recognition in mice

Cited by 40 publications

References 38 publications

Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse

Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

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