Combination of memantine and alpha7 nicotinic acetylcholine receptor ligands exerts superior efficacy over monotreatments to improve cognitive performance of aged rats

Combination treatments based on pharmacological interactions at 7 nAChRs are promising therapeutic approaches for neurocognitive disorders (NCDs). Memantine, an already approved medication in some NCDs, may not only act as an antagonist of the glutamatergic NMDA receptors (NMDAR) but also serve as an antagonist of the cholinergic 7 nAChRs. Here we set out to utilize a combination treatment regime with an 7 nAChR-selective agonist (PHA-543613) and a novel proprietary 7 nAChR ligand with marked positive allosteric modulator (PAM) activity (CompoundX). The cognitive efficacy of combination treatments was tested in a naturally aged rat model. Naturally aged rats showed marked cognitive decline in the novel object recognition (NOR) test, and they displayed pathological changes at the molecular level in terms of various inflammatory markers. In addition, aged rats also exhibited cholinergic changes such as mRNA upregulation of 7 nAChRs. Memantine-PHA-543613 and memantine-CompoundX combination treatments successfully alleviated the age-related decline of recognition memory of rats by exceeding the null-effects of the corresponding subtherapeutic levels of monotreatments. Results indicate a positive interaction between memantine and 7-nAChR agonists and PAMs, which reflects a prominent role of 7 nAChRs in the cognitive enhancement of combination treatments especially in age-related cognitive decline. Moreover, the putative direct action of memantine on 7 nAChRs may also contribute to the observed synergistic interaction between memantine and other selective 7 nAChR compounds.