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

0459355 - FGÚ 2017 RIV US eng J - Journal Article
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
Preferential Inhibition of Tonically over Phasically Activated NMDA Receptors by Pregnane Derivatives.
Journal of Neuroscience. Roč. 36, č. 7 (2016), s. 2161-2175. ISSN 0270-6474. E-ISSN 1529-2401
R&D Projects: GA ČR(CZ) GAP303/12/1464; GA ČR(CZ) GBP304/12/G069; GA TA ČR(CZ) TE01020028; GA ČR(CZ) GBP208/12/G016; GA MŠMT(CZ) EE2.3.30.0025; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:67985823 ; RVO:61388963
Keywords : memantine * neuroprotection * neurosteroid * NMDA receptor * pregnanolone sulfate * synaptic transmission
Subject RIV: ED - Physiology
Impact factor: 5.988, year: 2016

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.
Permanent Link: http://hdl.handle.net/11104/0259572