The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice.

Aurore Sors,Ali Krazem,Claire Letondor,Elisabeth Mocaer,Nadia Henkous,Takashi Yoshitake,Jan Kehr,Daniel J Béracochéa,Gaelle Dominguez

doi:10.3389/fphar.2016.00492

Abstract

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 histaminergic and cholinergic pathways, to create a synergistic effect. To that aim, 14 month old C57/Bl6 mice were administered per oesophagy during nine consecutive days with Donepezil (at 0.1 and 0.3 mg/kg) and S 38093 (at 0.1, 0.3, and 1.0 mg/kg), a H3 histaminergic antagonist developed by Servier, alone or in combination and tested for memory in a contextual memory task that modelized the age-induced memory dysfunction. The present study shows that the combination of Donepezil and S 38093 induced a dose-dependent synergistic memory-enhancing effect in middle-aged mice with a statistically higher size of effect never obtained with compounds alone and without any pharmacokinetic interaction between both compounds. We demonstrated that the memory-enhancing effect of the S 38093 and Donepezil combination is mediated by its action on the septo-hippocampal circuitry, since it canceled out the reduction of CREB phosphorylation (pCREB) observed in these brain areas in vehicle-treated middle-aged animals. Overall, the effects of drug combinations on pCREB in the hippocampus indicate that the synergistic promnesiant effects of the combination on memory performance in middle-aged mice stem primarily from an enhancement of neural activity in the septo-hippocampal system.

Highlights

The “cholinergic hypothesis” in aging or Alzheimer’s disease is based on the correlation between the memory impairment and the decrease of the cholinergic function in the brain (Bartus et al, 1982; Johannsson et al, 2015)
Since it has been shown that memory of D1 is hippocampus-dependent (Chauveau et al, 2008, 2010) whereas memory of D2 is dependent on the prefrontal cortex (PFC) activity (Chauveau et al, 2009), it is of importance to verify that any promnesiant impact of the combinations of compounds on D1 did not alter memory of D2
Even if the effect of the compounds were evaluated in the PFC and the ventral hippocampus in supplemental data, it was demonstrated that H3 antagonists including S 38093 as well as Donepezil were able to significantly increase ACh levels in other brain areas and in particular dorsal hippocampus (Medhurst et al, 2007; Herrik et al, 2016), a critical region for memory processes, in which we have demonstrated phosphorylated CREB (pCREB) increases in the present study

Summary

Introduction

The “cholinergic hypothesis” in aging or Alzheimer’s disease is based on the correlation between the memory impairment and the decrease of the cholinergic function in the brain (Bartus et al, 1982; Johannsson et al, 2015). Such correlation has been observed in aged rodents (Fu et al, 2014; Lim et al, 2015). Its activation leads to the inhibition of the synthesis and release of histamine (Arrang et al, 1983) and negatively regulates the release of other neurotransmitters such as ACh when H3 is expressed on heterologous nerve endings (Blandina et al, 1996; Brown et al, 2001). It has been argued that H3 antagonists, which could hamper the constitutive negative feedback of H3 receptors on the release of these neurotransmitters, would be valuable in correcting cognitive deficiencies (Fox et al, 2003; Ligneau et al, 2007; Femenía et al, 2015)

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