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

摘要

Drugs activating the sigma-1 (sigma(1)) chaperone protein are anti-amnesic and neuroprotective in neurodegenerative pathologies like Alzheimer's disease (AD). Since these so-called sigma(1) receptor (sigma(1) R) 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 sigma(1) agonist PRE-084, or the non-selective sigma(1) 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 A beta(25-35) 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 sigma(1) 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 alpha(7) nicotinic ACh receptors and sigma(1) R. These results demonstrated that sigma(1) drugs do not only offer a protective potential alone but also in combination with other therapeutic agents. The nature of neuromodulatoly molecular chaperone of the sigma(1) R could eventually lead to synergistic combinations. (C) 2015 Elsevier B.V. All rights reserved.