Modulation of GABA and glycine receptors in rat pyramidal hippocampal neurones by 3α5β-pregnanolone derivatives. (September 2018)

• Record Type: Journal Article
• Authors: Bukanova, Julia V.; Solntseva, Elena I.; Kolbaev, Sergey N.; Kudova, Eva
• Is Part Of: Neurochemistry international. Volume 118(2018)
• Page Start: 145
• Page End: 151
• Publication Date: 2018-09
• Subjects: Neurosteroid -- GABA receptor -- Glycine receptor -- Pregnanolone -- Structure-activity relationship; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2018.06.002
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: The ability of pregnanolone glutamate (PA-Glu), pregnanolone hemisuccinate (PA-hSuc) and pregnanolone hemipimelate (PA-hPim), neuroactive steroids with a negative modulatory effect on excitatory N -methyl-d -aspartate receptors, to influence the functional activity of inhibitory γ-aminobutyric acid and glycine receptors was estimated. The GABA- and glycine-induced chloride currents ( I GABA and I Gly ) were measured in isolated pyramidal neurons of the rat hippocampus using the patch-clamp technique. Compound PA-Glu was found to potentiate I GABA and to inhibit I Gly, while PA-hSuc and PA-hPim inhibited both I GABA and I Gly . Moreover, PA-Glu, PA-hSuc, and PA-hPim had a greater effect on desensitization than on the peak amplitude of I Gly . At a high concentration of glycine (500 μM), the effect of neurosteroids on the peak amplitude of I Gly disappeared, and the acceleration of desensitization remained. The conversion of PA-Glu into androstane glutamate (AND-Glu), an analogue that lacks the C-17 acetyl moiety, completely eliminated the effects on these receptors. Our results indicate that the C-17 acetyl moiety is crucial for the action on I GABA and I Gly . Our results indicate that the pregnanolone derivatives, in contrast to the androstane analogues, modulate I GABA and I Gly at low micromolar concentrations and this family of neurosteroids can be useful for future structure-activity relationship studies of the steroid modulation of other receptor types. Highlights: The GABA and glycine induced currents ( I GABA and I Gly ) were studied in rat neurons. New steroids with negative effect on NMDA receptors were studied on I GABA and I Gly . Pregnane steroids modulated I GABA and I Gly in low micromolar concentrations. Androstane steroids were not active for I GABA and I Gly . C-17 acetyl moiety is crucial for the action of steroids on I GABA and I Gly .