title: The pharmacology of tacrine at N-methyl-d-aspartate receptors.
abstract: The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca2+-activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease.
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Horak
authors.affiliation: National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
authors.forename: Kristina
authors.initials: K
authors.lastname: Holubova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Nepovimova
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Krusek
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Kaniakova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Vyklicky
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Ales
authors.initials: A
authors.lastname: Stuchlik
authors.affiliation: National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Ricny
authors.affiliation: National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Vales
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D013619:Tacrine
keywords: Cognition; Long term potentiation; M1 activation; Multi-target directed ligands; NMDA receptors; Tacrine