Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

Bukanova, Julia V.; Solntseva, E. I.; Kudová, Eva

doi:10.3389/fnmol.2020.00044

Cited by 8 publications

(4 citation statements)

References 47 publications

(62 reference statements)

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“…It can be assumed that some of these sites are responsible for desensitization and can interact with each other. The results of this work generally coincide with our previous results obtained on the same model with other steroids: pregnanes, androstanes, and androstenes . With those steroids, we reported the same tendency, i.e., higher potency of the substances to accelerate desensitization than to reduce the peak amplitude of I Gly .…”

Section: Discussionsupporting

confidence: 91%

“…The effects of NSs with pregnane and androstane structure on glycine-induced chloride current ( I Gly ) were studied on a culture of rat spinal neurons − and on recombinant GlyRs expressed in Xenopus oocytes. , Our recent studies described the effect of NSs on I Gly in isolated rat hippocampal pyramidal neurons. Using this model, we have shown that NSs with pregnane, androstane, and androstene structures decrease I Gly by accelerating desensitization and reducing peak amplitude. − The effects of corticosteroids on I Gly have not yet been investigated. In the present work, we studied the effect of ten corticosteroids and their derivatives on I Gly in isolated rat hippocampal pyramidal neurons.…”

Section: Introductionmentioning

confidence: 99%

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Corticosteroids as Selective and Effective Modulators of Glycine Receptors

Solntseva

Bukanova

Kondratenko

et al. 2023

ACS Chem. Neurosci.

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The mechanism of the negative impact of corticosteroids on the induction and progress of mental illness remains unclear. In this work, we studied the effects of corticosteroids on the activity of neuronal glycine receptors (GlyR) and GABA-A receptors (GABA A R) by measuring the chloride current induced by the application of GABA (2 or 5 μM) to isolated cerebellar Purkinje cells (I GABA ) and by the application of glycine (100 μM) to pyramidal neurons of the rat hippocampus (I Gly ). It was found that corticosterone, 5α-dihydrodeoxycorticosterone, allotetrahydrocorticosterone, cortisol, and 17α,21-dihydroxypregnenolone were able to accelerate the desensitization of the I Gly at physiological concentrations (IC 50 values varying from 0.39 to 0.72 μM). Next, cortisone, 11-deoxycortisol, 11-deoxycorticosterone, 5β-dihydrodeoxycorticosterone, and tetrahydrocorticosterone accelerated the desensitization of I Gly with IC 50 values varying from 10.3 to 15.2 μM. Allotetrahydrocorticosterone and tetrahydrocorticosterone potentiated the I GABA albeit with high EC 50 values (18−23 μM). The rest of the steroids had no effect on I GABA in the range of concentrations of 1−100 μM. Finally, our study has suggested a structural relationship of the 3β-hydroxyl group/3-oxo group with the selective modulatory activity on GlyRs in contrast to the 3α-hydroxyl group that is pivotal for GABA A Rs. In summary, our results suggest that increased GlyR desensitization by corticosteroids may contribute to brain dysfunction under chronic stress and identify corticosteroids for further development as selective modulators of GlyRs.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Corticosteroids as Selective and Effective Modulators of Glycine Receptors

Solntseva

Bukanova

Kondratenko

et al. 2023

ACS Chem. Neurosci.

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“…The results of our structure-activity relationship study will serve as a useful platform for understanding the mechanisms of physiological effects of pregnane NSs. Moreover, together with our previously published descriptive study of NSs with androstane skeleton (J. V. Bukanova et al, 2020) and the scheduled study on corticosteroids will afford comprehensive overview of the influence of endogenous steroids and NSs on the I GABA and I Gly . Rat pups were kept with their mother in separate cage with permanent access to manufactured complete feedstuff and water.…”

Section: Introductionmentioning

confidence: 95%

Pregnane neurosteroids exert opposite effects on GABA and glycine‐induced chloride current in isolated rat neurons

et al. 2022

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The ability of endogenous neurosteroids (NSs) with pregnane skeleton modified at positions C‐3 and C‐5 to modulate the functional activity of inhibitory glycine receptors (GlyR) and ionotropic ɣ‐aminobutyric acid receptors (GABAAR) was estimated. The glycine and GABA‐induced chloride current (IGly and IGABA) were measured in isolated pyramidal neurons of the rat hippocampus and in isolated rat cerebellar Purkinje cells, respectively. Our experiments demonstrated that pregnane NSs affected IGABA and IGly in a different manner. At low concentrations (up to 5 μM), tested pregnane NSs increased or did not change the peak amplitude of the IGABA, but reduced the IGly by decreasing the peak amplitude and/or accelerating desensitization. Namely, allopregnanolone (ALLO), epipregnanolone (EPI), pregnanolone (PA), pregnanolone sulfate (PAS) and 5β‐dihydroprogesterone (5β‐DHP) enhanced the IGABA in Purkinje cells. Dose–response curves plotted in the concentration range from 1 nM to 100 μM were smooth for EPI and 5β‐DHP, but bell‐shaped for ALLO, PA and PAS. The peak amplitude of the IGly was reduced by PA, PAS, and 5α‐ and 5β‐DHP. In contrast, ALLO, ISO and EPI did not modulate it. Dose–response curves for the inhibition of the IGly peak amplitude were smooth for all active compounds. All NSs accelerated desensitization of the IGly. The dose–response relationship for this effect was smooth for ALLO, PA, PAS and 5β‐DHP, but it was U‐shaped for EPI, 5α‐DHP and ISO. These results, together with our previous results on NSs with androstane skeleton, offer comprehensive overview for understanding the mechanisms of effects of NSs on IGly and IGABA.

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“…In the CNS, the best-known receptors modulated by NAS are type A γ-aminobutyric acid (GABA A ) receptors and glutamate receptors including NMDA receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors ( Joëls, 1997 ; Wu and Chen, 1997 ; Wu et al, 1998 ; Yaghoubi et al, 1998 ; Beyenburg et al, 2001 ; Rupprecht, 2003 ; Shirakawa et al, 2005 ). Furthermore, interactions of NAS with glycine, transient receptor potential (TRP), nicotinic acetylcholine, muscarinic acetylcholine, sigma (σ)-receptors and several types of voltage-gated calcium channel were reported ( Klangkalya and Chan, 1988 ; Valera et al, 1992 ; Monnet et al, 1995 ; Hu et al, 2007 ; Xu et al, 2008 ; Majeed et al, 2012 ; Bukanova et al, 2020 ).…”

Section: Mechanism Of Action Of Neuroactive Steroidsmentioning

confidence: 99%

Steroid Sulfation in Neurodegenerative Diseases

Vítků

Hill

Kolátorová

et al. 2022

Front. Mol. Biosci.

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Steroid sulfation and desulfation participates in the regulation of steroid bioactivity, metabolism and transport. The authors focused on sulfation and desulfation balance in three neurodegenerative diseases: Alzheimer´s disease (AD), Parkinson´s disease (PD), and multiple sclerosis (MS). Circulating steroid conjugates dominate their unconjugated counterparts, but unconjugated steroids outweigh their conjugated counterparts in the brain. Apart from the neurosteroid synthesis in the central nervous system (CNS), most brain steroids cross the blood-brain barrier (BBB) from the periphery and then may be further metabolized. Therefore, steroid levels in the periphery partly reflect the situation in the brain. The CNS steroids subsequently influence the neuronal excitability and have neuroprotective, neuroexcitatory, antidepressant and memory enhancing effects. They also exert anti-inflammatory and immunoprotective actions. Like the unconjugated steroids, the sulfated ones modulate various ligand-gated ion channels. Conjugation by sulfotransferases increases steroid water solubility and facilitates steroid transport. Steroid sulfates, having greater half-lives than their unconjugated counterparts, also serve as a steroid stock pool. Sulfotransferases are ubiquitous enzymes providing massive steroid sulfation in adrenal zona reticularis and zona fasciculata.. Steroid sulfatase hydrolyzing the steroid conjugates is exceedingly expressed in placenta but is ubiquitous in low amounts including brain capillaries of BBB which can rapidly hydrolyze the steroid sulfates coming across the BBB from the periphery. Lower dehydroepiandrosterone sulfate (DHEAS) plasma levels and reduced sulfotransferase activity are considered as risk factors in AD patients. The shifted balance towards unconjugated steroids can participate in the pathophysiology of PD and anti-inflammatory effects of DHEAS may counteract the MS.

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Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

Cited by 8 publications

References 47 publications

Corticosteroids as Selective and Effective Modulators of Glycine Receptors

Corticosteroids as Selective and Effective Modulators of Glycine Receptors

Pregnane neurosteroids exert opposite effects on GABA and glycine‐induced chloride current in isolated rat neurons

Steroid Sulfation in Neurodegenerative Diseases

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