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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F16%3A00459355" target="_blank" >RIV/67985823:_____/16:00459355 - isvavai.cz</a>

Alternative codes found

RIV/61388963:_____/16:00459355 RIV/00216208:11320/16:10388127

Result on the web

<a href="http://dx.doi.org/10.1523/JNEUROSCI.3181-15.2016" target="_blank" >http://dx.doi.org/10.1523/JNEUROSCI.3181-15.2016</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1523/JNEUROSCI.3181-15.2016" target="_blank" >10.1523/JNEUROSCI.3181-15.2016</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

ED - Physiology

OECD FORD branch

—

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Neuroscience

ISSN

0270-6474

e-ISSN

—

Volume of the periodical

36

Issue of the periodical within the volume

7

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

2161-2175

UT code for WoS article

000370818700009

EID of the result in the Scopus database

2-s2.0-84958817737