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Strömberg, Jessica
Publications (8 of 8) Show all publications
Johansson, M., Strömberg, J., Ragagnin, G., Doverskog, M. & Bäckström, T. (2016). GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo. Journal of Steroid Biochemistry and Molecular Biology, 160(SI), 98-105.
Open this publication in new window or tab >>GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo
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2016 (English)In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 160, no SI, 98-105 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2016
Keyword
Allopregnanolone, Neurosteroids, GABAA receptor, GAMSA, Cognition
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-118532 (URN)10.1016/j.jsbmb.2015.10.019 (DOI)000376840500013 ()26523675 (PubMedID)
Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2017-11-30Bibliographically approved
Johansson, M., Agusti, A., Llansola, M., Montoliu, C., Strömberg, J., Malinina, E., . . . Felipo, V. (2015). GR3027 antagonizes GABA(A) receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy. American Journal of Physiology - Gastrointestinal and Liver Physiology, 309(5), G400-G409.
Open this publication in new window or tab >>GR3027 antagonizes GABA(A) receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy
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2015 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 309, no 5, G400-G409 p.Article in journal (Refereed) Published
Abstract [en]

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 GABA(A) 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 GABA(A) receptors by neurosteroids such as allopregnanolone and 3 alpha, 21-dihydroxy-5 alpha-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.

Place, publisher, year, edition, pages
American Physiological Society, 2015
Keyword
GABA(A) receptors, hyperammonemia, neurosteroids, hepatic encephalopathy
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-109375 (URN)10.1152/ajpgi.00073.2015 (DOI)000360687000012 ()26138462 (PubMedID)
Note

This study was financed by Umecrine Cognition AB

Available from: 2015-09-28 Created: 2015-09-25 Last updated: 2017-12-01Bibliographically approved
Strömberg, J., Lundgren, P., Taube, M., Bäckström, T., Wang, M. & Haage, D. (2009). The effect of the neuroactive steroid 5β-pregnane-3β, 20(R)-diol on the time course of GABA evoked currents is different to that of pregnenolone sulphate. European Journal of Pharmacology, 605(1-3), 78-86.
Open this publication in new window or tab >>The effect of the neuroactive steroid 5β-pregnane-3β, 20(R)-diol on the time course of GABA evoked currents is different to that of pregnenolone sulphate
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2009 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 605, no 1-3, 78-86 p.Article in journal (Refereed) Published
Abstract [en]

The endogenous progesterone metabolite allopregnanolone has a number of properties including anesthetic, sedative, antiepileptic, anxiolytic, impaired memory function and negative mood symptoms. Allopregnanolone is a potent positive GABA(A) receptor function modulators. In contrast, 3beta-hydroxy-steroids (3beta-steroids) usually modulate the GABA(A) receptor negatively. They have attracted some interest for their possible use as therapeutic agents that could counteract the negative symptoms induced by allopregnanolone. Two hypotheses for the action of 3beta-steroids have been proposed: 1) 3beta-steroids act in a similar way to pregnenolone sulphate, which non-competitively reduces GABA(A) receptor activity. 2) 3beta-steroids specifically antagonize the effect of allopregnanolone. We have therefore tried to clarify this issue by comparing the effect of pregnenolone sulphate and 5beta-pregnane-3beta, 20(R)-diol on the GABA-evoked currents by the patch clamp technique on neurons from the medial preoptic nucleus. Both pregnenolone sulphate and 5beta-pregnane-3beta, 20(R)-diol increase the desensitization rate of the current response evoked by a 2 s GABA application. However, their effects on other parameters of the GABA evoked currents differed in degree and sometimes even in direction. The actions of pregnenolone sulphate and 5beta-pregnane-3beta, 20(R)-diol were not altered in the presence of allopregnanolone, which indicates that they do not directly interact with allopregnanolone. In addition, when 5beta-pregnane-3beta, 20(R)-diol was tested on spontaneous inhibitory postsynaptic currents (sIPSCs), it dramatically reduced the allopregnanolone-induced prolongation of the decay time constant but it had no effect on the decay under control conditions. In conclusion, the effect of 5beta-pregnane-3beta, 20(R)-diol on GABA-evoked currents is different to that of pregnenolone sulphate in medial preoptic nucleus neurons.

Keyword
Patch clamp; sIPSCs; Tau decay; Desensitization; (Rat)
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-36809 (URN)10.1016/j.ejphar.2008.12.038 (DOI)19168059 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2017-12-12Bibliographically approved
Strömberg, J., Haage, D., Taube, M., Bäckström, T. & Lundgren, P. (2006). Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor. Neuroscience, 143(1), 73-81.
Open this publication in new window or tab >>Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor
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2006 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 143, no 1, 73-81 p.Article in journal (Refereed) Published
Keyword
Analysis of Variance, Animals, Brain/cytology, Cells; Cultured, Chloride Channels/drug effects/physiology, Chlorides/metabolism, Dose-Response Relationship; Drug, Drug Interactions, Male, Membrane Potentials/drug effects/physiology/radiation effects, Neurons/*drug effects/physiology, Patch-Clamp Techniques/methods, Pregnanolone/*pharmacology, Rats, Rats; Wistar, Receptors; GABA-A/*metabolism, Steroids/*pharmacology, gamma-Aminobutyric Acid/*pharmacology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-10000 (URN)10.1016/j.neuroscience.2006.07.031 (DOI)16938407 (PubMedID)
Available from: 2008-06-04 Created: 2008-06-04 Last updated: 2017-12-14Bibliographically approved
Strömberg, J., Bäckström, T. & Lundgren, P. (2005). Rapid non-genomic effect of glucocorticoid metabolites and neurosteroids on the gamma-aminobutyric acid-A receptor. European Journal of Neuroscience, 21(8), 2083-2088.
Open this publication in new window or tab >>Rapid non-genomic effect of glucocorticoid metabolites and neurosteroids on the gamma-aminobutyric acid-A receptor
2005 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 21, no 8, 2083-2088 p.Article in journal (Other academic) Published
Keyword
Animals, Cerebral Cortex/*cytology, Chlorides/metabolism, Desoxycorticosterone/*analogs & derivatives/pharmacology, Dose-Response Relationship; Drug, Drug Interactions, Glucocorticoids/*metabolism/*pharmacology, Male, Neurons/*cytology/drug effects/metabolism, Pregnanolone/pharmacology, Rats, Rats; Wistar, Receptors; GABA-A/*metabolism, Synaptosomes/*drug effects, gamma-Aminobutyric Acid/pharmacology
Identifiers
urn:nbn:se:umu:diva-9999 (URN)10.1111/j.1460-9568.2005.04047.x (DOI)15869504 (PubMedID)
Available from: 2008-06-04 Created: 2008-06-04 Last updated: 2017-12-14Bibliographically approved
Lundgren, P., Strömberg, J., Bäckström, T. & Wang, M. (2003). Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3beta-hydroxy-5alpha-pregnane-20-one (isoallopregnanolone). Brain Research, 982(1), 45-53.
Open this publication in new window or tab >>Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3beta-hydroxy-5alpha-pregnane-20-one (isoallopregnanolone)
2003 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 982, no 1, 45-53 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-2183 (URN)10.1016/S0006-8993(03)02939-1 (DOI)12915239 (PubMedID)
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2017-12-14Bibliographically approved
Bäckström, T., Andersson, A., Andreén, L., Birzniece, V., Bixo, M., Björn, I., . . . Zingmark, E. (2003). Pathogenesis in menstrual cycle-linked CNS disorders.. Annals of the New York Academy of Sciences, 1007, 42-53.
Open this publication in new window or tab >>Pathogenesis in menstrual cycle-linked CNS disorders.
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2003 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1007, 42-53 p.Article, review/survey (Other academic) Published
Keyword
Affect/physiology, Animals, Female, Humans, Menstrual Cycle/*physiology, Mood Disorders/*etiology/physiopathology/psychology, Pregnanolone/physiology, Premenstrual Syndrome/*etiology/physiopathology/psychology, Receptors; GABA-A/physiology
Identifiers
urn:nbn:se:umu:diva-16450 (URN)10.1196/annals.1286.005 (DOI)14993039 (PubMedID)
Available from: 2007-09-28 Created: 2007-09-28 Last updated: 2017-12-14Bibliographically approved
Strömberg, J., Lundgren, P., Taube, M., Bäckström, T., Wang, M. & Haage, D.The neuroactive steroid 5beta-pregnane-3beta, 20(R)-diol alters the kinetic properties of the GABA-A receptor differently from pregnenolone-sulfate. .
Open this publication in new window or tab >>The neuroactive steroid 5beta-pregnane-3beta, 20(R)-diol alters the kinetic properties of the GABA-A receptor differently from pregnenolone-sulfate
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2185 (URN)
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2015-11-11Bibliographically approved
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