Abstract
Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction.
Highlights
The role of acetylcholine is well established in cognition processes since the blockade of muscarinic cholinergic receptors by scopolamine impairs the encoding of new memories (Atri et al 2004) whereas the activation of nicotinic cholinergic receptors by cholinergic agonists enhances the encoding of new information (Levin et al 2006)
The present results provide evidence that S 47445 given alone possesses cognitive-enhancing properties after repeated administration in two different tasks based on aging-induced memory deficits in mice, the contextual serial discrimination (CSD), and a working memory model using radial maze
The cognitive impairments observed in the present study in middle-aged and aged animals are in accordance with our previous studies, showing that young adult 4–5-month-old mice exhibited significant and substantial memory performance in those tasks, as compared to middle-aged and aged animals (Béracochéa et al, 2007; Marighetto et al 2008a, b; Mingaud et al 2008; Vandesquille et al 2011; Sors et al 2017)
Summary
The role of acetylcholine is well established in cognition processes (for review, see Hasselmo 2006) since the blockade of muscarinic cholinergic receptors by scopolamine impairs the encoding of new memories (Atri et al 2004) whereas the activation of nicotinic cholinergic receptors by cholinergic agonists enhances the encoding of new information (Levin et al 2006).Since neurodegenerative processes impacting cholinergic pathways were reported in the brains of Alzheimer’s disease (AD) (Bartus et al 1982; Davies and Maloney 1976), acetylcholinesterase inhibitors (as donepezil) which inhibit the breakdown of acetylcholine were initially developed and remain the standard treatment of cognitive impairment in AD. Positive allosteric modulators of AMPA receptors (AMPA-PAMs) have been developed more in the last 10 years (Morrow et al 2006; Ward et al, 2010; Pirotte et al, 2013) They were shown to slow desensitization of AMPA receptors and enhance synaptic excitatory currents, thereby promoting synaptic transmission and plasticity (Black 2005; Morrow et al 2006; Lynch and Gall 2006; O’Neill and Dix 2007; Partin 2015). They were reported to facilitate episodic and spatial working memories in a number of behavioral studies in rodents, monkeys, and humans, both memories known to be early impaired in AD patients (Bernard et al 2010; Black 2005; Morrow et al 2006; Lynch and Gall 2006; O’Neill and Dix 2007; Partin 2015)
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