Efficacy of THN201, a Combination of Donepezil and Mefloquine, to Reverse Neurocognitive Deficits in Alzheimer's Disease.

Marine Droguerre,Michel Hamon,Benjamin Portal,Mathieu Charvériat,Nicole Déglon,Vanessa Villard,Adeline Duchêne,Bruno P Guiard,Camille Lejards,Johann Meunier,Christèle Picoli,Franck Mouthon

doi:10.3389/fnins.2020.00563

Abstract

Donepezil (DPZ) is an acetylcholinesterase inhibitor used in Alzheimer’s disease to restore cognitive functions but is endowed with limited efficacy. Recent studies pointed out the implication of astroglial networks in cognitive processes, notably via astrocyte connexins (Cxs), proteins involved in gap junction intercellular communications. Hence, we investigated the impact on cognition of pharmacological or genetic modulations of those astrocyte Cxs during DPZ challenge in two rodent models of Alzheimer’s disease–like memory deficits. We demonstrated that the Cx modulator mefloquine (MEF) significantly enhanced the procognitive effect of DPZ in both models. In parallel, we determined that MEF potentiated DPZ-induced release of acetylcholine in hippocampus. Finally, local genetic silencing of astrocyte Cxs in the hippocampus was also found to enhance the procognitive effect of DPZ, pointing out the importance of Cx-dependent astrocyte networks in memory processes.

Highlights

Alzheimer’s disease (AD) is characterized by the loss of cognitive functions especially learning, working, and spatial memory (Mattila et al, 2012)
Brains from AD patients are notably distinguished by senile plaques composed of amyloid β (Aβ) protein and a marked deficit in acetylcholine (ACh) notably in the hippocampus (Shinotoh et al, 2000)
Similar observations were made in mice that received treatment of DPZ0.25 p.o., which did not reverse scopolamine-induced deficit (P = 0.69; Figure 1C), but the same low dose of DPZ combined with MEF at 3 or 10 mg/kg p.o., significantly reversed the alternation deficit, up to that noted in vehicle-treated controls, suggesting a potential synergistic effect of MEF and DPZ on working memory after a scopolamine challenge

Summary

Introduction

Alzheimer’s disease (AD) is characterized by the loss of cognitive functions especially learning, working, and spatial memory (Mattila et al, 2012). Brains from AD patients are notably distinguished by senile plaques composed of amyloid β (Aβ) protein and a marked deficit in acetylcholine (ACh) notably in the hippocampus (Shinotoh et al, 2000). Donepezil (DPZ), a potent acetylcholinesterase (AChE) inhibitor, is currently one of the most widely used for AD in the world (Adlimoghaddam et al, 2018). Through its reversible binding to AChE, DPZ promotes cholinergic neurotransmission, thereby alleviating cognitive impairments. Only modest improvements were found in patients, and the development of novel therapeutic approaches is eagerly needed (Deardorff et al, 2015).

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