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7-Methoxyderivative of tacrine is a 'foot-in-the-door' open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo
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SYSNO ASEP 0492869 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název 7-Methoxyderivative of tacrine is a 'foot-in-the-door' open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo Tvůrce(i) Kaniaková, Martina (UEM-P)
Kletečková, L. (CZ)
Lichnerová, Katarina (UEM-P)
Holubová, K. (CZ)
Skřenková, Kristýna (UEM-P)
Kořínek, M. (CZ)
Krůšek, J. (CZ)
Smejkalová, T. (CZ)
Korabecný, J. (CZ)
Valeš, K. (CZ)
Soukup, O. (CZ)
Horák, Martin (UEM-P) RID, ORCIDZdroj.dok. Neuropharmacology. - : Elsevier - ISSN 0028-3908
Roč. 140, sep 15 (2018), s. 217-232Poč.str. 16 s. Jazyk dok. eng - angličtina Země vyd. NL - Nizozemsko Klíč. slova behavioural experiment ; electrophysiology ; glutamate receptor ; human pathogenic mutation ; ion channel ; pharmacology Vědní obor RIV FH - Neurologie, neurochirurgie, neurovědy Obor OECD Neurosciences (including psychophysiology Institucionální podpora UEM-P - RVO:68378041 UT WOS 000445717100021 EID SCOPUS 85053054975 DOI 10.1016/j.neuropharm.2018.08.010 Anotace N-methyl-D-aspartate receptors /NMDARs/ are ionotropic glutamate receptors that mediate excitatory neuro-transmission in the mammalian central nervous system /CNS/, and their dysregulation results in the aetiology of many CNS syndromes. Several NMDAR modulators have been used successfully in clinical trials /including memantine/ and NMDARs remain a promising pharmacological target for the treatment of CNS syndromes. 1,2,3,4-Tetrahydro-9-aminoacridine /tacrine, THA/ was the first approved drug for Alzheimers disease /AD/ treatment. 7-methoxyderivative of THA /7-MEOTA/ is less toxic and showed promising results in patients with tardive dyskinesia. We employed electrophysiological recordings in HEK293 cells and rat neurones to examine the mechanism of action of THA and 7-MEOTA at the NMDAR. We showed that both THA and 7-MEOTA are foot-in-the-door open-channel blockers of GluNl/GluN2 receptors and that 7-MEOTA is a more potent but slower blocker than THA. We found that the IC50 values for THA and 7-MEOTA exhibited the GluN1/GIuN2A < GluNl/G1uN2B < GluN1/GluN2C = GluN1/GluN2D relationship and that 7-MEOTA effectively inhibits human GluNl/GluN2A-M817V receptors that carry a pathogenic mutation. We also showed that 7-MEOTA is a foot-in-the-door open-channel blocker of GluNl/GluN3 receptors, although these receptors were not inhibited by memantine. In addition, the inhibitory potency of 7-MEOTA at synaptic and extrasynaptic hippocampal NMDAR5 was similar, and 7-MEOTA exhibited better neuroprotective activity when compared with THA and memantine in rats with NMDA-induced lesions of the hippocampus. Finally, intraperitoneal administration of 7-MEOTA attenuated MK-801-induced hyperlocomotion and pre-pulse inhibition deficit in rats. We conclude that 7-MEOTA may be considered for the treatment of diseases associated with the dysfunction of NMDARs. Pracoviště Ústav experimentální medicíny Kontakt Lenka Koželská, lenka.kozelska@iem.cas.cz, Tel.: 241 062 218, 296 442 218 Rok sběru 2019
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