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

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.

Pharmaco-fUS for Characterizing Drugs for Alzheimer’s Disease – The Case of THN201, a Drug Combination of Donepezil Plus Mefloquine

“…When MEF was co-administered with DPZ at low dose, a similar decreasing effect was observed, although less widespread as it appeared to be restricted to the hippocampus and some parts of the cortex. In line with our previous behavioral data ( Droguerre et al, 2020 ), this hemodynamic pattern suggests a synergistic effect of the combination rather than possible additive effects that both drugs would produce on their own. Indeed, in the hippocampus, non-significant effects of MEF1 or DPZ0.25 alone corresponded to trends toward a CBV increase, in sharp contrast with the significant CBV decrease observed in mice injected with the THN201 combination or DPZ1 ( Figure 1E ).…”

“…To the best of our knowledge, our study is the first report of fUS for investigating the effects of psychoactive compounds in animal groups large enough ( n = 8–9 mice per group) to allow statistical evaluations. DPZ at the 0.25 mg/kg dose produced only very limited, if any, changes of CBV, in line with the lack of procognitive effect of this dose that we reported recently ( Droguerre et al, 2020 ). In contrast, DPZ at the precognitive dose of 1 mg/kg induced widespread and persistent CBV decreases.…”

“…Our data with the latter drug are consistent with a previous pharmacological MRI study in rats ( Hegedus et al, 2015 ) that reported a weak increasing effect of DPZ on the BOLD signal at low dose but a long-lasting inhibition of BOLD signal at a higher dose). Interestingly, DPZ1 and THN201-induced decreases of CBV in the hippocampus occurred in the same doses’ ranges as those producing clear-cut precognitive effects in mouse AD models ( Droguerre et al, 2020 ). This close correlation might well be underlain through drug-induced changes in acetylcholine outflow because high concentrations of this neurotransmitter were reported to activate hippocampal inhibitory interneurons ( McQuiston, 2014 ) and we previously observed a marked acetylcholine overflow at hippocampal level in mice administered with THN201 or DPZ1 ( Droguerre et al, 2020 ).…”

“…Interestingly, DPZ1 and THN201-induced decreases of CBV in the hippocampus occurred in the same doses’ ranges as those producing clear-cut precognitive effects in mouse AD models ( Droguerre et al, 2020 ). This close correlation might well be underlain through drug-induced changes in acetylcholine outflow because high concentrations of this neurotransmitter were reported to activate hippocampal inhibitory interneurons ( McQuiston, 2014 ) and we previously observed a marked acetylcholine overflow at hippocampal level in mice administered with THN201 or DPZ1 ( Droguerre et al, 2020 ). In support of this interpretation, a recent neuroimaging study did show that acetylcholine reduced in vivo neuronal activity and produced a decreased fMRI response at its injection site in brain ( Zaldivar et al, 2018 ).…”

“…Meanwhile, previous non-clinical and clinical studies demonstrated that the modulation of astroglial connexins may enhance efficacy of drugs in neurological disorders ( Duchêne et al, 2016 ; Jeanson et al, 2016 ; Vodovar et al, 2018 ; Sauvet et al, 2019 ). Importantly, we recently demonstrated that mefloquine, a connexin modulator, both used in vitro ( Picoli et al, 2012 , 2019 ) and in vivo ( Jeanson et al, 2016 ; Droguerre et al, 2019 ), significantly potentiated the efficacy of one of the gold standard treatments in AD, donepezil ( Adlimoghaddam et al, 2018 ), both in scopolamine and amyloid-beta (Aβ) rodent models ( Droguerre et al, 2020 ).…”