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

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.

Histamine 3 receptor inverse agonist Samelisant (SUVN-G3031): Pharmacological characterization of an investigational agent for the treatment of cognitive disorders

“…The doses were several-fold lower than the dose that mediated the functional effects at H3 receptor. S 38093 also potentiated the procognitive effects of donepezil (Sors et al, 2016). The observed effects of S 38093 may also have been mediated through the sigma-1 receptors (see above).…”

“…JNJ-10181457 significantly attenuated the scopolamine-induced memory deficits in delayed non-matching to position task in rats (Galici et al, 2009). In a contextual serial discrimination task, S 38093 significantly reversed the memory deficits associated with ageing, and further a synergistic effect on cognition was observed when co-administered with donepezil in mice (Panayi et al, 2017;Sors et al, 2016). Ciproxifan attenuated the memory deficits caused by chronic restraint stress in object recognition and passive avoidance tasks in rats (Trofimiuk and Braszko, 2014).…”

HIV-1 gp120 impairs spatial memory through CREB

“…However, we found that the injection of rolipram in the presence of HIV-1 gp120 restored memory. Donepezil, a CREB inducer, also restored memory (data not shown) (47). Brains were collected from these mice and protein extracts were isolated from the hippocampal area and then subjected to western blot analysis.…”

Co-treatment With the Herbal Medicine SIP3 and Donepezil Improves Memory and Depression in the Mouse Model of Alzheimer’s Disease

“…Based on these results, we conducted MWM test on animals at the late stage of dementia to compare cognitive abilities between the two groups [40]. In the SIP3L co-treatment group, the time to reach the target quadrant was shorter and the time spent in the target quadrant was longer, indicating that the animals in this group had a more improved cognitive ability than those treated with donepezil alone [41,42].…”