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Bäckström, TorbjörnORCID iD iconorcid.org/0000-0002-0907-3535
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Publications (10 of 180) Show all publications
Bäckström, T., Doverskog, M., Blackburn, T. P., Scharschmidt, B. F. & Felipo, V. (2024). Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment. Neuroscience and Biobehavioral Reviews, 161, Article ID 105668.
Open this publication in new window or tab >>Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment
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2024 (English)In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 161, article id 105668Article, review/survey (Refereed) Published
Abstract [en]

Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Astrocytes, Cognitive disorders, GABA-A receptor, Microglia, Neuroinflammation, Steroid-PAMs
National Category
Neurology Neurosciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-223649 (URN)10.1016/j.neubiorev.2024.105668 (DOI)38608826 ()2-s2.0-85190158099 (Scopus ID)
Funder
EU, Horizon 2020, 721802
Available from: 2024-04-22 Created: 2024-04-22 Last updated: 2024-04-22Bibliographically approved
Sandström, A., Bixo, M., Bäckström, T., Möller, A. & Turkmen, S. (2023). Altered GABAA receptor function in women with endometriosis: a possible pain-related mechanism. Acta Obstetricia et Gynecologica Scandinavica, 102(10), 1316-1322
Open this publication in new window or tab >>Altered GABAA receptor function in women with endometriosis: a possible pain-related mechanism
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2023 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 102, no 10, p. 1316-1322Article in journal (Refereed) Published
Abstract [en]

Introduction: The mechanism underlying endometriosis-related pain remains poorly understood. Previous studies have indicated that γ-aminobutyric acid (GABA) type A (GABAA) receptors and GABAergic substances (eg endogenous neurosteroids) play important mechanistic roles in various pain conditions. Our primary objective was to compare GABAA receptor function between women with endometriosis and healthy controls by performing a challenge test with diazepam, a GABAA receptor agonist, using the saccadic eye velocity as the main outcome. The secondary objective was to investigate the relationship between GABAA receptor function and serum levels of allopregnanolone, an endogenous positive modulator of the GABAA receptor, in the participating women.

Material and methods: 15 women with pelvic pain and laparoscopically confirmed endometriosis and 10 healthy, symptom-free, control women, aged 18–40 years, underwent the diazepam challenge test during the follicular phase of the menstrual cycle. Basal serum allopregnanolone levels were measured prior to diazepam injection.

Results: Compared with healthy controls, women with pelvic pain and confirmed endometriosis had a significantly smaller change in saccadic eye velocity after GABAA receptor stimulation with diazepam, indicating lower sensitivity to diazepam. The saccadic eye velocity response was not correlated with the serum allopregnanolone levels.

Conclusions: Women with painful endometriosis show altered GABAA receptor function, depicted as a muted response to an exogenous GABAA receptor agonist.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
allopregnanolone, central sensitisation, endometriosis, GABA, pain
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-206360 (URN)10.1111/aogs.14559 (DOI)000954282800001 ()36944570 (PubMedID)2-s2.0-85150900704 (Scopus ID)
Available from: 2023-04-26 Created: 2023-04-26 Last updated: 2023-12-19Bibliographically approved
Bäckström, T., Bäckström, D. C. & Joshi, S. (2023). Effects of hormones on seizure expression (3ed.). In: Jerome Engel; Solomon L. Moshe (Ed.), Epilepsy: a comprehensive textbook (pp. 779-792). New York: Wolters Kluwer
Open this publication in new window or tab >>Effects of hormones on seizure expression
2023 (Swedish)In: Epilepsy: a comprehensive textbook / [ed] Jerome Engel; Solomon L. Moshe, New York: Wolters Kluwer, 2023, 3, p. 779-792Chapter in book (Refereed)
Place, publisher, year, edition, pages
New York: Wolters Kluwer, 2023 Edition: 3
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-222604 (URN)9781975105525 (ISBN)
Available from: 2024-03-22 Created: 2024-03-22 Last updated: 2024-03-26Bibliographically approved
Bengtsson, S. K. S., Sjöstedt, J., Malinina, E., Das, R., Doverskog, M., Johansson, I.-M., . . . Bäckström, T. (2023). Extra-synaptic GABAA receptor potentiation and neurosteroid-induced learning deficits are inhibited by GR3027, a GABAA modulating steroid antagonist. Biomolecules, 13(10), Article ID 1496.
Open this publication in new window or tab >>Extra-synaptic GABAA receptor potentiation and neurosteroid-induced learning deficits are inhibited by GR3027, a GABAA modulating steroid antagonist
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2023 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 13, no 10, article id 1496Article in journal (Refereed) Published
Abstract [en]

Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5β3γ2L and α1β2γ2L GABAA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the Dynaflow™ application system. With α5β3γ2L receptors, 0.01–3 μM GR3027, in a concentration-dependent manner, reduced the current response induced by 200 nM THDOC + 0.3 µM GABA, as well as the THDOC-induced direct gated effect. GR3027 (1 μM) alone had no effect on the GABA-mediated current response or current in the absence of GABA. With α1β2γ2L receptors, GR3027 alone had no effect on the GABA-mediated current response or did not affect the receptor by itself. Meanwhile, 1–3 µM GR3027 reduced the current response induced by 200 nM THDOC + 30 µM GABA and 3 µM GR3027 that induced by 200 nM THDOC when GABA was not present. Objectives In Vivo: GR3027 reduces allopregnanolone (AP)-induced decreased learning and anesthesia in male Wistar rats. Rats treated i.v. with AP (2.2 mg/kg) or vehicle were given GR3027 in ratios of 1:0.5 to 1:5 dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin. A dose ratio of AP:GR3027 of at least 1:2.5 antagonized the AP-induced decreased learning in the Morris Water Mase (MWM) and 1:7.5 antagonized the loss of righting reflex (LoR). GR3027 treatment did not change other functions in the rat compared to the vehicle group. Conclusions: GR3027 functions in vitro as an inhibitor of GABAA receptors holding α5β3γ2L and α1β2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP’s negative effects on LoR and learning in the MWM.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
allopregnanolone, GABAA receptor, GR3027 improves memory, memory impairment, THDOC
National Category
Physiology
Identifiers
urn:nbn:se:umu:diva-216186 (URN)10.3390/biom13101496 (DOI)37892178 (PubMedID)2-s2.0-85175017097 (Scopus ID)
Funder
EU, Horizon 2020, 721802
Available from: 2023-11-09 Created: 2023-11-09 Last updated: 2024-03-18Bibliographically approved
Bäckström, T., Bengtsson, S. K. S., Sjöstedt, J., Malinina, E., Johansson, I.-M., Ragagnin, G., . . . Lundgren, P. (2023). Isoallopregnanolone inhibits estrus cycle-dependent aggressive behavior. Biomolecules, 13(6), Article ID 1017.
Open this publication in new window or tab >>Isoallopregnanolone inhibits estrus cycle-dependent aggressive behavior
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2023 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 13, no 6, article id 1017Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
allopregnanolone, diestrus, estrus, estrus cycle, estrus cycle-dependent aggression, isoallopregnanolone, resident/intruder test, Wistar rats
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-212055 (URN)10.3390/biom13061017 (DOI)001014229000001 ()37371597 (PubMedID)2-s2.0-85164023779 (Scopus ID)
Funder
EU, Horizon 2020, 721802Swedish Research Council, 4x-11198Umeå UniversityVästerbotten County Council
Available from: 2023-07-18 Created: 2023-07-18 Last updated: 2024-03-18Bibliographically approved
Bäckström, T., Turkmen, S., Das, R., Doverskog, M. & Blackburn, T. P. (2023). The GABA system, a new target for medications against cognitive impairment—Associated with neuroactive steroids. Journal of Internal Medicine, 294(3), 281-294
Open this publication in new window or tab >>The GABA system, a new target for medications against cognitive impairment—Associated with neuroactive steroids
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2023 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 294, no 3, p. 281-294Article, review/survey (Refereed) Published
Abstract [en]

The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
allopregnanolone, dementia, GABA-A receptor, memory, neurosteroids
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-212756 (URN)10.1111/joim.13705 (DOI)001039236600001 ()37518841 (PubMedID)2-s2.0-85166405771 (Scopus ID)
Funder
EU, Horizon 2020, 721802
Available from: 2023-08-11 Created: 2023-08-11 Last updated: 2024-03-18Bibliographically approved
Mincheva, G., Gimenez-Garzo, C., Izquierdo-Altarejos, P., Martinez-Garcia, M., Doverskog, M., Blackburn, T. P., . . . Felipo, V. (2022). Golexanolone, a GABAA receptor modulating steroid antagonist, restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation. CNS Neuroscience & Therapeutics, 28(11), 1861-1874
Open this publication in new window or tab >>Golexanolone, a GABAA receptor modulating steroid antagonist, restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation
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2022 (English)In: CNS Neuroscience & Therapeutics, ISSN 1755-5930, E-ISSN 1755-5949, Vol. 28, no 11, p. 1861-1874Article in journal (Refereed) Published
Abstract [en]

Aims: Hyperammonemic rats show peripheral inflammation, increased GABAergic neurotransmission and neuroinflammation in cerebellum and hippocampus which induce motor incoordination and cognitive impairment. Neuroinflammation enhances GABAergic neurotransmission in cerebellum by enhancing the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways. Golexanolone reduces GABAA receptors potentiation by allopregnanolone. This work aimed to assess if treatment of hyperammonemic rats with golexanolone reduces peripheral inflammation and neuroinflammation and restores cognitive and motor function and to analyze underlying mechanisms.

Methods: Rats were treated with golexanolone and effects on peripheral inflammation, neuroinflammation, TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways, and cognitive and motor function were analyzed.

Results: Hyperammonemic rats show increased TNFα and reduced IL-10 in plasma, microglia and astrocytes activation in cerebellum and hippocampus, and impaired motor coordination and spatial and short-term memories. Treating hyperammonemic rats with golexanolone reversed changes in peripheral inflammation, microglia and astrocytes activation and restored motor coordination and spatial and short-term memory. This was associated with reversal of the hyperammonemia-enhanced activation in cerebellum of the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways.

Conclusion: Reducing GABAA receptors activation with golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in hyperammonemic rats. The effects identified would also occur in patients with hepatic encephalopathy and, likely, in other pathologies associated with neuroinflammation.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
GR3027, inflammation, minimal hepatic encephalopathy, motor incoordination, spatial memory
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-198340 (URN)10.1111/cns.13926 (DOI)000829810900001 ()35880480 (PubMedID)2-s2.0-85134680360 (Scopus ID)
Available from: 2022-08-01 Created: 2022-08-01 Last updated: 2023-04-26Bibliographically approved
Bäckström, T., Kjølhede, P. & Landgren, B.-M. (Eds.). (2022). Gynekologi (3ed.). Lund: Studentlitteratur AB
Open this publication in new window or tab >>Gynekologi
2022 (Swedish)Collection (editor) (Other academic)
Place, publisher, year, edition, pages
Lund: Studentlitteratur AB, 2022. p. 503 Edition: 3
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-197724 (URN)978-91-44-14419-1 (ISBN)
Available from: 2022-07-04 Created: 2022-07-04 Last updated: 2022-07-06Bibliographically approved
Das, R., Ragagnin, G., Sjöstedt, J., Johansson, I.-M., Haage, D., Druzin, M., . . . Bäckström, T. (2022). Medroxyprogesterone acetate positively modulates specific GABAA-receptor subtypes - affecting memory and cognition. Psychoneuroendocrinology, 141, Article ID 105754.
Open this publication in new window or tab >>Medroxyprogesterone acetate positively modulates specific GABAA-receptor subtypes - affecting memory and cognition
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2022 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 141, article id 105754Article in journal (Refereed) Published
Abstract [en]

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 GABAA-receptor modulatory effects and are known to affect memory, learning, appetite, and mood. In women, 4 years chronic treatment with MPA doubles the frequency of dementia and in rats, MPA causes cognitive impairment related to the GABAergic system. Activation of the membrane bound GABAA receptor results in a chloride ion flux that can be studied by whole-cell patch-clamp electrophysiological recordings. The purpose of this study was to clarify the modulatory effects of MPA and specific MPA metabolites, with structures like known GABAA-receptor modulators, on different GABAA-receptor subtypes. An additional aim was to verify the results as steroid effects on GABA response in single cells taken from rat hypothalamus. HEK-293 cell-lines permanently expressing the recombinant human GABAA-receptor subtype α1β2γ2L or α5β3γ2L or α2β3γ2S were created. The MPA metabolites 3α5α-MPA,3β5α-MPA and 3β5β-MPA were synthesised and purified for electrophysiological patch-clamp measurements with a Dynaflow system. The effects of MPA and tetrahydrodeoxycorticosterone were also studied. None of the studied MPA metabolites affected the responses mediated by α1β2γ2L or α5β3γ2L GABAA receptors. Contrary, MPA clearly acted both as a positive modulator and as a direct activator of the α5β3γ2L and α2β3γ2S GABAA receptors. However, in concentrations up to 10 μM, MPA was inactive at the α1β2γ2L GABAA receptor. In the patch-clamp recordings from dissociated cells of the preoptic area in rats, MPA increased the amplitude of responses to GABA. In addition, MPA alone without added GABA, evoked a current response. In conclusion, MPA acts as a positive modulator of specific GABAA receptor subtypes expressed in HEK cells and at native GABA receptors in single cells from the hypothalamic preoptic area.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Alpha5 GABA-A receptor, Dementia, GABA-A receptor, Medroxyprogesterone-acetate, Neurosteroids, Positive GABA-AR modulator
National Category
Physiology
Identifiers
urn:nbn:se:umu:diva-194529 (URN)10.1016/j.psyneuen.2022.105754 (DOI)000806353300010 ()35395561 (PubMedID)2-s2.0-85128809630 (Scopus ID)
Funder
EU, Horizon 2020, 721802
Available from: 2022-05-10 Created: 2022-05-10 Last updated: 2023-09-05Bibliographically approved
Bäckström, T. (2022). Menstruationscykelbundna tillstånd (3ed.). In: Torbjörn Bäckström; Preben Kjølhede; Britt-Marie Landgren (Ed.), Gynekologi: (pp. 89-96). Lund: Studentlitteratur AB
Open this publication in new window or tab >>Menstruationscykelbundna tillstånd
2022 (Swedish)In: Gynekologi / [ed] Torbjörn Bäckström; Preben Kjølhede; Britt-Marie Landgren, Lund: Studentlitteratur AB, 2022, 3, p. 89-96Chapter in book (Other academic)
Place, publisher, year, edition, pages
Lund: Studentlitteratur AB, 2022 Edition: 3
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-197717 (URN)978-91-44-14419-1 (ISBN)
Available from: 2022-07-04 Created: 2022-07-04 Last updated: 2023-05-03Bibliographically approved
Projects
Basis for sex and stress hormone induced mood symptoms and diseases [2009-02637_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0907-3535

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