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Article ; Online: Isoallopregnanolone Inhibits Estrus Cycle-Dependent Aggressive Behavior.

Bäckström, Torbjörn / Bengtsson, Sara K S / Sjöstedt, Jessica / Malinina, Evgenya / Johansson, Maja / Ragagnin, Gianna / Ekberg, Karin / Lundgren, Per

Biomolecules

2023 Volume 13, Issue 6

Abstract: Among female rats, some individuals show estrus cycle-dependent irritability/aggressive behaviors, and these individual rats may be used as a model for premenstrual dysphoric disorder (PMDD). We wanted to investigate if these behaviors are related to the ...

Abstract	Among female rats, some individuals show estrus cycle-dependent irritability/aggressive behaviors, and these individual rats may be used as a model for premenstrual dysphoric disorder (PMDD). We wanted to investigate if these behaviors are related to the estrus cycle phase containing moderately increased levels of positive GABA-A receptor-modulating steroids (steroid-PAM), especially allopregnanolone (ALLO), and if the adverse behavior can be antagonized. The electrophysiology studies in this paper show that isoallopregnanolone (ISO) is a GABA-A-modulating steroid antagonist (GAMSA), meaning that ISO can antagonize the agonistic effects of positive GABA-A receptor-modulating steroids in both α1β2γ2L and α4β3δ GABA-A receptor subtypes. In this study, we also investigated whether ISO could antagonize the estrus cycle-dependent aggressive behaviors in female Wistar rats using a resident-intruder test. Our results confirmed previous reports of estrus cycle-dependent behaviors in that 42% of the tested rats showed higher levels of irritability/aggression at diestrus compared to those at estrus. Furthermore, we found that, during the treatment with ISO, the aggressive behavior at diestrus was alleviated to a level comparable to that of estrus. We noticed an 89% reduction in the increase in aggressive behavior at diestrus compared to that at estrus. Vehicle treatment in the same animals showed a minimal effect on the diestrus-related aggressive behavior. In conclusion, we showed that ISO can antagonize Steroid-PAM both in α1β2γ2L and α4β3δ GABA-A receptor subtypes and inhibit estrus cycle-dependent aggressive behavior.
MeSH term(s)	Rats ; Female ; Animals ; Rats, Wistar ; Receptors, GABA-A ; Aggression/physiology ; Estrus ; Pregnanolone/pharmacology
Chemical Substances	Receptors, GABA-A ; Pregnanolone (BXO86P3XXW)
Language	English
Publishing date	2023-06-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13061017
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Article ; Online: Medroxyprogesterone acetate positively modulates specific GABA

Das, Roshni / Ragagnin, Gianna / Sjöstedt, Jessica / Johansson, Maja / Haage, David / Druzin, Michael / Johansson, Staffan / Bäckström, Torbjörn

Psychoneuroendocrinology

2022 Volume 141, Page(s) 105754

Abstract: Medroxyprogesterone acetate (MPA) is a progestin widely used in humans as hormone replacement therapy and at other indications. Many progestin metabolites, as the progesterone metabolite allopregnanolone, have ... ...

Abstract	Medroxyprogesterone acetate (MPA) is a progestin widely used in humans as hormone replacement therapy and at other indications. Many progestin metabolites, as the progesterone metabolite allopregnanolone, have GABA
MeSH term(s)	Animals ; Cognition ; Female ; HEK293 Cells ; Humans ; Medroxyprogesterone Acetate/pharmacology ; Progestins ; Rats ; Receptors, GABA-A/metabolism ; gamma-Aminobutyric Acid/metabolism ; gamma-Aminobutyric Acid/pharmacology
Chemical Substances	Progestins ; Receptors, GABA-A ; gamma-Aminobutyric Acid (56-12-2) ; Medroxyprogesterone Acetate (C2QI4IOI2G)
Language	English
Publishing date	2022-03-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	197636-9
ISSN	1873-3360 ; 0306-4530
ISSN (online)	1873-3360
ISSN	0306-4530
DOI	10.1016/j.psyneuen.2022.105754
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Zs.A 1235: Show issues

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Book ; Online ; Thesis: N-containing fluorous ligands for aerobic oxidations in fluorous biphasic systems

Ragagnin, Gianna

2003

Author's details	Gianna Ragagnin
Keywords	Oxidation ; Katalysator ; Fluororganische Verbindungen ; Flüssig-Flüssig-System
Language	English
Size	Online-Ressource
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Univ., Diss--München, 2003
Database	Former special subject collection: coastal and deep sea fishing

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Article ; Online: GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo.

Johansson, Maja / Strömberg, Jessica / Ragagnin, Gianna / Doverskog, Magnus / Bäckström, Torbjörn

The Journal of steroid biochemistry and molecular biology

2016 Volume 160, Page(s) 98–105

Abstract: GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), ... ...

Abstract	GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAA receptor-mediated currents. On the contrary, various 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents. Allopregnanolone and THDOC have both negative and positive actions. Allopregnanolone can impair encoding/consolidation and retrieval of memories. Chronic administration of a physiological allopregnanolone concentration reduces cognition in mice models of Alzheimer's disease. In humans an allopregnanolone challenge impairs episodic memory and in hepatic encephalopathy cognitive deficits are accompanied by increased brain ammonia and allopregnanolone. Hippocampal slices react in vitro to ammonia by allopregnanolone synthesis in CA1 neurons, which blocks long-term potentiation (LTP). Thus, allopregnanolone may impair learning and memory by interfering with hippocampal LTP. Contrary, pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye-blink conditioning in mice. In rat the GAMSA UC1011 inhibits an allopregnanolone-induced learning impairment and the GAMSA GR3027 restores learning and motor coordination in rats with hepatic encephalopathy. In addition, the GAMSA isoallopregnanolone antagonizes allopregnanolone-induced anesthesia in rats, and in humans it antagonizes allopregnanolone-induced sedation and reductions in saccadic eye velocity. 17PA is also an effective GAMSA in vivo, as it antagonizes allopregnanolone-induced anesthesia and spinal analgesia in rats. In vitro the allopregnanolone/THDOC-increased GABA-mediated GABAA receptor activity is antagonized by isoallopregnanolone, UC1011, GR3027 and 17PA, while the effect of GABA itself is not affected.
MeSH term(s)	Animals ; Desoxycorticosterone/analogs & derivatives ; Desoxycorticosterone/metabolism ; Evoked Potentials/drug effects ; GABA-A Receptor Antagonists/pharmacology ; Humans ; Learning/drug effects ; Memory/drug effects ; Pregnanolone/metabolism ; Receptors, GABA-A/metabolism ; Saccades/drug effects
Chemical Substances	GABA-A Receptor Antagonists ; Receptors, GABA-A ; Desoxycorticosterone (40GP35YQ49) ; tetrahydrodeoxycorticosterone (4AB717DP4A) ; Pregnanolone (BXO86P3XXW)
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1049188-0
ISSN	1879-1220 ; 0960-0760
ISSN (online)	1879-1220
ISSN	0960-0760
DOI	10.1016/j.jsbmb.2015.10.019
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Zs.A 708: Show issues

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Article ; Online: GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy.

Johansson, Maja / Agusti, Ana / Llansola, Marta / Montoliu, Carmina / Strömberg, Jessica / Malinina, Evgenya / Ragagnin, Gianna / Doverskog, Magnus / Bäckström, Torbjörn / Felipo, Vicente

American journal of physiology. Gastrointestinal and liver physiology

2015 Volume 309, Issue 5, Page(s) G400–9

Abstract: Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and ... ...

Abstract	Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations. Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions. We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids such as allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC). This work aimed to assess whether GR3027 improves motor incoordination, spatial learning, and circadian rhythms of activity in rats with HE. GR3027 was administered subcutaneously to two main models of HE: rats with chronic hyperammonemia due to ammonia feeding and rats with portacaval shunts (PCS). Motor coordination was assessed in beam walking and spatial learning and memory in the Morris water maze and the radial maze. Circadian rhythms of ambulatory and vertical activity were also assessed. In both hyperammonemic and PCS rats, GR3027 restores motor coordination, spatial memory in the Morris water maze, and spatial learning in the radial maze. GR3027 also partially restores circadian rhythms of ambulatory and vertical activity in PCS rats. GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE.
MeSH term(s)	Animals ; Circadian Rhythm ; Desoxycorticosterone/analogs & derivatives ; Desoxycorticosterone/pharmacology ; Drug Antagonism ; HEK293 Cells ; Hepatic Encephalopathy/drug therapy ; Humans ; Hydroxysteroids/pharmacology ; Hydroxysteroids/therapeutic use ; Hyperammonemia/drug therapy ; Locomotion ; Male ; Maze Learning ; Pregnanolone/pharmacology ; Rats ; Rats, Wistar ; Receptors, GABA-A/metabolism
Chemical Substances	Hydroxysteroids ; Receptors, GABA-A ; Desoxycorticosterone (40GP35YQ49) ; tetrahydrodeoxycorticosterone (4AB717DP4A) ; Pregnanolone (BXO86P3XXW)
Language	English
Publishing date	2015-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603840-2
ISSN	1522-1547 ; 0193-1857
ISSN (online)	1522-1547
ISSN	0193-1857
DOI	10.1152/ajpgi.00073.2015
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Uc I Zs.89: Show issues

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Article: Aerobic Ru-Catalyzed Epoxidations in Fluorous Biphasic System Using New Fluorous Benzimidazolic Ligands

Ragagnin, Gianna / Knochel, Paul

Synlett

2004 Volume 2004, Issue 06, Page(s) 951–954

Abstract: An efficient ruthenium catalyzed fluorous biphasic epoxidation of alkenes with oxygen in the presence of a pyridine-benzimidazole ligand bearing perfluorinated ponytails is described. Excellent yields and reaction rates were obtained and the fluorous ... ...

Abstract	An efficient ruthenium catalyzed fluorous biphasic epoxidation of alkenes with oxygen in the presence of a pyridine-benzimidazole ligand bearing perfluorinated ponytails is described. Excellent yields and reaction rates were obtained and the fluorous phase could be recycled up to ten times without any loss of activity.
Keywords	aerobic epoxidations ; catalysis ; ruthenium ; fluorous biphasic system ; benzimidazoles
Language	English
Publishing date	2004-03-25
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	2042012-2
ISSN	1437-2096 ; 0936-5214
ISSN (online)	1437-2096
ISSN	0936-5214
DOI	10.1055/s-2004-820042
Database	Thieme publisher's database

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Article ; Online: A comparison of the pharmacological properties of recombinant human and rat alpha(1)beta(2)gamma(2L) GABA(A) receptors in Xenopus oocytes.

Rahman, Mozibur / Borra, Vijaya B / Isaksson, Monica / Johansson, Inga-Maj / Ragagnin, Gianna / Bäckström, Torbjörn / Wang, Ming-De

Clinical and experimental pharmacology & physiology

2008 Volume 35, Issue 9, Page(s) 1002–1011

Abstract: In the present study, we compared the pharmacology, particularly neurosteroid modulation of the GABA(A) receptor, between human and rat alpha(1)beta(2)gamma(2)(L) GABA(A) receptors and between human receptors containing the long (L) and short (S) forms ... ...

Abstract	In the present study, we compared the pharmacology, particularly neurosteroid modulation of the GABA(A) receptor, between human and rat alpha(1)beta(2)gamma(2)(L) GABA(A) receptors and between human receptors containing the long (L) and short (S) forms of the gamma(2)-subunit. We observed that maximum responses to GABA were significantly higher with the human alpha(1)beta(2)gamma(2)(L) receptor compared with the rat receptor. In terms of neurosteroid modulation, increases in the EC(15) response to GABA induced by 3alpha-OH-5beta-pregnan-20-one (3alpha5betaP), 5alpha-androstane-3alpha,17beta-diol (3alpha5alphaADL) and 5alpha-pregnane-3alpha,20beta-diol (3alpha5alpha-diol) were significantly greater for the rat compared with the human receptor. Responses to 30 micromol/L GABA were inhibited by 3beta-OH-5alpha-pregnan-20-one (UC1010) and 5beta-pregnan-3beta,20(R)-diol (UC1020) to a greater degree for human and rat receptors, respectively. Responses to GABA + 3alpha5alphaTHDOC were inhibited by 5alpha-pregnan-3beta,20(S)-diol (UC1019) and pregnenolone sulphate to a greater degree for human and rat receptors, respectively. The GABA dose-response curves for human alpha(1)beta(2)gamma(2)(S) and alpha(1)beta(2)gamma(2)(L) receptors were identical. However, the maximum GABA-evoked current, the direct gating effect of pentobarbital and the allosteric potentiation of the GABA EC(15) response by 3alpha5alphaTHDOC and 3alpha5betaP were significantly higher with alpha(1)beta(2)gamma(2)(S) than alpha(1)beta(2)gamma(2)(L) receptors. Inhibition of the response to 30 micromol/L GABA by UC1010 and UC1020 was greater for a(1)beta(2)gamma(2)(L) and alpha(1)beta(2)gamma(2)(S) receptors, respectively. Inhibition of responses to 3alpha5alphaTHDOC + GABA by UC1019 and UC1010 was significantly higher for alpha(1)beta(2)gamma(2)(L) receptors. In conclusion, the site of activation by GABA and neurosteroid modulation differ between human and rat alpha(1)beta(2)gamma(2)(L) receptors, as well as between human receptors containing the L and S splice variants of the gamma(2)-subunit.
MeSH term(s)	Allosteric Regulation/drug effects ; Allosteric Regulation/physiology ; Animals ; Catalytic Domain/drug effects ; Cloning, Molecular ; Electrophysiology ; Female ; GABA-A Receptor Agonists ; GABA-A Receptor Antagonists ; Humans ; Oocytes/drug effects ; Oocytes/metabolism ; Oocytes/physiology ; Pregnenolone/pharmacology ; Protein Isoforms/agonists ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Protein Isoforms/pharmacology ; Protein Subunits/agonists ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Protein Subunits/pharmacology ; Rats ; Receptors, GABA-A/genetics ; Receptors, GABA-A/metabolism ; Recombinant Proteins/agonists ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Recombinant Proteins/pharmacology ; Xenopus laevis
Chemical Substances	GABA-A Receptor Agonists ; GABA-A Receptor Antagonists ; Protein Isoforms ; Protein Subunits ; Receptors, GABA-A ; Recombinant Proteins ; pregnenolone sulfate (04Y4D91RG0) ; Pregnenolone (73R90F7MQ8)
Language	English
Publishing date	2008-09
Publishing country	Australia
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	189277-0
ISSN	1440-1681 ; 0305-1870 ; 0143-9294
ISSN (online)	1440-1681
ISSN	0305-1870 ; 0143-9294
DOI	10.1111/j.1440-1681.2008.04946.x
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Zs.A 990: Show issues

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Article: Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems.

Birzniece, Vita / Bäckström, Torbjörn / Johansson, Inga-Maj / Lindblad, Charlotte / Lundgren, Per / Löfgren, Magnus / Olsson, Tommy / Ragagnin, Gianna / Taube, Magdalena / Turkmen, Sahruh / Wahlström, Göran / Wang, Ming-De / Wihlbäck, Anna-Carin / Zhu, Di

Brain research reviews

2006 Volume 51, Issue 2, Page(s) 212–239

Abstract: This article will review neuroactive steroid effects on serotonin and GABA systems, along with the subsequent effects on cognitive functions. Neurosteroids (such as estrogen, progesterone, and allopregnanolone) are synthesized in the central and ... ...

Abstract	This article will review neuroactive steroid effects on serotonin and GABA systems, along with the subsequent effects on cognitive functions. Neurosteroids (such as estrogen, progesterone, and allopregnanolone) are synthesized in the central and peripheral nervous system, in addition to other tissues. They are involved in the regulation of mood and memory, in premenstrual syndrome, and mood changes related to hormone replacement therapy, as well as postnatal and major depression, anxiety disorders, and Alzheimer's disease. Estrogen and progesterone have their respective hormone receptors, whereas allopregnanolone acts via the GABA(A) receptor. The action of estrogen and progesterone can be direct genomic, indirect genomic, or non-genomic, also influencing several neurotransmitter systems, such as the serotonin and GABA systems. Estrogen alone, or in combination with antidepressant drugs affecting the serotonin system, has been related to improved mood and well being. In contrast, progesterone can have negative effects on mood and memory. Estrogen alone, or in combination with progesterone, affects the brain serotonin system differently in different parts of the brain, which can at least partly explain the opposite effects on mood of those hormones. Many of the progesterone effects in the brain are mediated by its metabolite allopregnanolone. Allopregnanolone, by changing GABA(A) receptor expression or sensitivity, is involved in premenstrual mood changes; and it also induces cognitive deficits, such as spatial-learning impairment. We have shown that the 3beta-hydroxypregnane steroid UC1011 can inhibit allopregnanolone-induced learning impairment and chloride uptake potentiation in vitro and in vivo. It would be important to find a substance that antagonizes allopregnanolone-induced adverse effects.
MeSH term(s)	Animals ; Brain/drug effects ; Brain/metabolism ; Brain/physiopathology ; Cognition/drug effects ; Cognition Disorders/chemically induced ; Cognition Disorders/metabolism ; Cognition Disorders/physiopathology ; Gonadal Steroid Hormones/adverse effects ; Gonadal Steroid Hormones/metabolism ; Humans ; Learning/drug effects ; Neural Pathways/drug effects ; Neural Pathways/metabolism ; Neural Pathways/physiopathology ; Receptors, GABA-A/metabolism ; Serotonin/metabolism ; gamma-Aminobutyric Acid/metabolism
Chemical Substances	Gonadal Steroid Hormones ; Receptors, GABA-A ; Serotonin (333DO1RDJY) ; gamma-Aminobutyric Acid (56-12-2)
Language	English
Publishing date	2006-08
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	423722-5
ISSN	1872-6321 ; 0165-0173
ISSN (online)	1872-6321
ISSN	0165-0173
DOI	10.1016/j.brainresrev.2005.11.001
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