PT  - JOURNAL ARTICLE
AU  - Vojtech Vyklicky
AU  - Tereza Smejkalova
AU  - Barbora Krausova
AU  - Ales Balik
AU  - Miloslav Korinek
AU  - Jirina Borovska
AU  - Martin Horak
AU  - Marketa Chvojkova
AU  - Lenka Kleteckova
AU  - Karel Vales
AU  - Jiri Cerny
AU  - Michaela Nekardova
AU  - Hana Chodounska
AU  - Eva Kudova
AU  - Ladislav Vyklicky
TI  - Preferential Inhibition of Tonically over Phasically Activated NMDA Receptors by Pregnane Derivatives
AID  - 10.1523/JNEUROSCI.3181-15.2016
DP  - 2016 Feb 17
TA  - The Journal of Neuroscience
PG  - 2161--2175
VI  - 36
IP  - 7
4099  - http://www.jneurosci.org/content/36/7/2161.short
4100  - http://www.jneurosci.org/content/36/7/2161.full
SO  - J. Neurosci.2016 Feb 17; 36
AB  - 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.SIGNIFICANCE STATEMENT Synaptic activation of N-methyl-d-aspartate receptors (NMDARs) plays a key role in synaptic plasticity, but excessive tonic NMDAR activation mediates excitotoxicity associated with many neurological disorders. Therefore, there is much interest in pharmacological agents capable of selectively blocking tonically activated NMDARs while leaving synaptically activated NMDARs intact. Here, we show that an endogenous neurosteroid pregnanolone sulfate is more potent at inhibiting tonically than synaptically activated NMDARs. Further, we report that a novel synthetic analog of pregnanolone sulfate, pregnanolone hemipimelate, inhibits tonic NMDAR currents without inhibiting the NMDAR component of the EPSC and shows neuroprotective activity in vivo without inducing psychomimetic side effects. These results suggest steroids may have a clinical advantage over other known classes of NMDAR inhibitors.