Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments

• σ1 Protein agonists (PRE-084, ANAVEX2-73) are neuroprotective and anti-amnesic in Aβ25–35-treated mice.
• Their combination with the AChE inhibitor donepezil, but not with the NMDA receptor antagonist memantine, shows synergy for neuroprotective effects.
• The synergy involves combined action at α7 nAChR and σ1R.
• Symptomatic effects are purely additive.

Drugs activating the sigma-1 (σ1) chaperone protein are anti-amnesic and neuroprotective in neurodegenerative pathologies like Alzheimer's disease (AD). Since these so-called σ1 receptor (σ1R) agonists modulate cholinergic and glutamatergic systems in a variety of physiological responses, we addressed their putative additive/synergistic action in combination with cholinergic or glutamatergic drugs. The selective σ1 agonist PRE-084, or the non-selective σ1 drug ANAVEX2-73 was combined with the acetylcholinesterase inhibitor donepezil or the NMDA receptor antagonist memantine in the nontransgenic mouse model of AD-like memory impairments induced by intracerebroventricular injection of oligomeric Aβ25–35 peptide. Two behavioral tests, spontaneous alternation and passive avoidance response, were used in parallel and both protective and symptomatic effects were examined. After determination of the minimally active doses for each compound, the combinations were tested and the combination index (CI) calculated. Combinations between the σ1 agonists and donepezil showed a synergic protective effect, with CI < 1, whereas the combinations with memantine showed an antagonist effect, with CI > 1. Symptomatic effects appeared only additive for all combinations, with CI = 1. A pharmacological analysis of the PRE-084 + donepezil combination revealed that the synergy could be due to an inter-related mechanism involving α7 nicotinic ACh receptors and σ1R. These results demonstrated that σ1 drugs do not only offer a protective potential alone but also in combination with other therapeutic agents. The nature of neuromodulatory molecular chaperone of the σ1R could eventually lead to synergistic combinations.