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Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments.
Behav Brain Res. 2016 Jan 01; 296:270-278.BB

Abstract

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Maurice T
Molecular Mechanisms in Neurodegenerative Diseases, MMDN Laboratory, Institut National de la Recherche et de la Santé Médicale, unit 1198, 34095 Montpellier, France; University of Montpellier, 34095 Montpellier, France; Ecole Pratique des Hautes Etudes, 75014 Paris, France. Electronic address: maurice@univ-montp2.fr.

MeSH

Amyloid beta-PeptidesAnimalsCholinesterase InhibitorsDisease Models, AnimalDonepezilDrug SynergismExcitatory Amino Acid AntagonistsFuransIndansMaleMemantineMemory DisordersMiceMorpholinesNeuroprotective AgentsPeptide FragmentsPiperidinesReceptors, N-Methyl-D-AspartateReceptors, sigma

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26386305

Citation

Maurice, Tangui. "Protection By Sigma-1 Receptor Agonists Is Synergic With Donepezil, but Not With Memantine, in a Mouse Model of Amyloid-induced Memory Impairments." Behavioural Brain Research, vol. 296, 2016, pp. 270-278.
Maurice T. Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments. Behav Brain Res. 2016;296:270-278.
Maurice, T. (2016). Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments. Behavioural Brain Research, 296, 270-278. https://doi.org/10.1016/j.bbr.2015.09.020
Maurice T. Protection By Sigma-1 Receptor Agonists Is Synergic With Donepezil, but Not With Memantine, in a Mouse Model of Amyloid-induced Memory Impairments. Behav Brain Res. 2016 Jan 1;296:270-278. PubMed PMID: 26386305.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments. A1 - Maurice,Tangui, Y1 - 2015/09/16/ PY - 2015/07/23/received PY - 2015/09/11/revised PY - 2015/09/15/accepted PY - 2015/9/20/entrez PY - 2015/9/20/pubmed PY - 2016/9/16/medline KW - Alzheimer's disease KW - Donepezil KW - Memantine KW - Memory KW - Neuroprotection KW - σ(1) Protein SP - 270 EP - 278 JF - Behavioural brain research JO - Behav Brain Res VL - 296 N2 - 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. SN - 1872-7549 UR - https://www.unboundmedicine.com/medline/citation/26386305/Protection_by_sigma_1_receptor_agonists_is_synergic_with_donepezil_but_not_with_memantine_in_a_mouse_model_of_amyloid_induced_memory_impairments_ DB - PRIME DP - Unbound Medicine ER -