Preferential Inhibition of Tonically over Phasically Activated NMDA Receptors by Pregnane Derivatives

Vyklický, Vojtěch; Smejkalová, Tereza; Krausová, Barbora; Balík, Aleš; Kořínek, Miloslav; Borovská, Jiřina; Horák, Martin; Chvojková, Markéta; Kletečková, Lenka; Valeš, Karel; Černý, Jiří; Nekardová, Michaela; Chodounská, Hana; Kudová, Eva; Vyklický ml., Ladislav

doi:https://dx.doi.org/10.1523/JNEUROSCI.3181-15.2016

Number of the records: 1

Preferential Inhibition of Tonically over Phasically Activated NMDA Receptors by Pregnane Derivatives

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SYSNO ASEP	0459355
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Preferential Inhibition of Tonically over Phasically Activated NMDA Receptors by Pregnane Derivatives
Author(s)	Vyklický, Vojtěch (FGU-C)_{RID, ORCID, SAI} Smejkalová, Tereza (FGU-C)_{RID, ORCID} Krausová, Barbora (FGU-C)_ORCID Balík, Aleš (FGU-C)_{RID, ORCID} Kořínek, Miloslav (FGU-C)_{RID, ORCID} Borovská, Jiřina (FGU-C) Horák, Martin (FGU-C)_{RID, ORCID} Chvojková, Markéta (FGU-C)_{RID, ORCID} Kletečková, Lenka (FGU-C)_ORCID Valeš, Karel (FGU-C)_{RID, ORCID, SAI} Černý, Jiří (FGU-C)_{RID, ORCID} Nekardová, Michaela (UOCHB-X)_RID Chodounská, Hana (UOCHB-X)_{RID, ORCID} Kudová, Eva (UOCHB-X)_{RID, ORCID} Vyklický ml., Ladislav (FGU-C)_{RID, ORCID, SAI}
Source Title	Journal of Neuroscience. - : Society for Neuroscience - ISSN 0270-6474 Roč. 36, č. 7 (2016), s. 2161-2175
Number of pages	15 s.
Language	eng - English
Country	US - United States
Keywords	memantine ; neuroprotection ; neurosteroid ; NMDA receptor ; pregnanolone sulfate ; synaptic transmission
Subject RIV	ED - Physiology
R&D Projects	GAP303/12/1464 GA ČR - Czech Science Foundation (CSF)
	GBP304/12/G069 GA ČR - Czech Science Foundation (CSF)
	TE01020028 GA TA ČR - Technology Agency of the Czech Republic (TA ČR)
	GBP208/12/G016 GA ČR - Czech Science Foundation (CSF)
	EE2.3.30.0025 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	FGU-C - RVO:67985823 ; UOCHB-X - RVO:61388963
UT WOS	000370818700009
EID SCOPUS	84958817737
DOI	10.1523/JNEUROSCI.3181-15.2016
Annotation	Postsynaptic N-methyl-D-aspartate receptors (NMDARs) phasically activated by presynaptically released glutamate are critical for synaptic transmission and plasticity. However, under pathological conditions, excessive activation of NMDARs by tonically increased ambient glutamate contributes to excitotoxicity associated with various acute and chronic neurological disorders. Here, using heterologously expressed GluN1/GluN2A and GluN1/GluN2B receptors and rat autaptic hippocampal microisland cultures, we show that pregnanolone sulfate inhibits NMDAR currents induced by a prolonged glutamate application with a higher potency than the NMDAR component of EPSCs. For synthetic pregnanolone derivatives substituted with a carboxylic acid moiety at the end of an aliphatic chain of varying length and attached to the steroid skeleton at C3, the difference in potency between tonic and phasic inhibition increased with the length of the residue. The steroid with the longest substituent, pregnanolone hemipimelate, had no effect on phasically activated receptors while inhibiting tonically activated receptors. In behavioral tests, pregnanolone hemipimelate showed neuroprotective activity without psychomimetic symptoms. These results provide insight into the influence of steroids on neuronal function and stress their potential use in the development of novel therapeutics with neuroprotective action.
Workplace	Institute of Physiology
Contact	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Year of Publishing	2017

Number of the records: 1