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  • 1.
    Birzniece, Vita
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundgren, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ragagnin, Gianna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Taube, Magdalena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Wang, Ming-De
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems.2006In: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 51, no 2, p. 212-239Article in journal (Refereed)
  • 2.
    Birzniece, Vita
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Türkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    GABA(A) receptor changes in acute allopregnanolone tolerance2006In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 535, no 1-3, p. 125-134Article in journal (Refereed)
    Abstract [en]

    To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.

  • 3.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andersson, Agneta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andreén, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Björn, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Haage, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Isaksson, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlott
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundgren, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ödmark, Inga-Stina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zingmark, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Pathogenesis in menstrual cycle-linked CNS disorders.2003In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1007, p. 42-53Article, review/survey (Other academic)
  • 4.
    Johansson, I-M
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Olsson, T
    Bäckström, T
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone inhibits learning in the Morris water maze2002In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 934, no 2, p. 125-131Article in journal (Refereed)
    Abstract [en]

    The progesterone metabolite allopregnanolone (3alpha-OH-5alpha-pregnane-20-one) inhibits neural functions, enhancing the GABA induced GABA(A) receptor activation. This effect is benzodiazepine like and benzodiazepines are known to impair memory. Acute effects of allopregnanolone on the hippocampus dependent spatial learning in the Morris water maze have not been studied. Adult male Wistar rats where injected (i.v.) with allopregnanolone (2 mg/kg), or vehicle, daily for 11 days. At 8 or 20 min after each injection, studies of place navigation were performed in the Morris water maze. Allopregnanolone concentrations in plasma and in nine different brain areas where analyzed by radioimmunoassay. The latency to find the platform was increased 8 min after the allopregnanolone injection, while normal learning was seen after 20 min. Swim speed did not differ between groups. A higher number of rats were swimming close to the pool wall (thigmotaxis) in the 8 min allopregnanolone group compared to the other groups. Allopregnanolone concentrations in the brain tissue at 8 min were 1.5 to 2.5 times higher then at 20 min after the allopregnanolone injections. After vehicle injections the brain concentrations of allopregnanolone were at control levels. Plasma concentrations of allopregnanolone followed the same pattern as in the brain, with the exception of an increase 8 min after vehicle injections. The natural progesterone metabolite allopregnanolone can inhibit learning in the Morris water maze, an effect not caused by motor impairment. The learning impairment might be due to a combination of changed swimming behavior and difficulties in navigation.

  • 5.
    Lindquist, David
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Aglund, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Survival-data for endometrial cancer patients in northern Sweden 2010-20112015In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, no 9, p. 1100-1100Article in journal (Other academic)
  • 6.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus2015In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 10, no 6, p. 3565-3572Article in journal (Refereed)
    Abstract [en]

    The incidence rate of tonsillar cancer is increasing worldwide. The current study identifies a parallel increase in the incidence of tonsillar cancer, human papilloma virus (HPV) and p16 expression among a population from northern Sweden, a sparsely populated area, confirming the strong association between p16 and HPV infection in tonsillar tissue. Data from the Swedish Cancer Registry was assessed to identify cases of tonsillar cancer in the northern territorial area of Sweden. HPV DNA was extracted from paraffin embedded diagnostic biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of p16 was identified by immunochemistry. Patients were grouped into urban or rural residence categories. A total of 214 cases were identified, comprising 155 (72.4%) men and 59 (27.6%) women, and 65 of these patients, who presented between 2000 and 2012, were analyzed. The overall median age for the analyzed patients was 58 years; 48 (74%) were males (median age, 57.5 years) and 17 (26%) were females (median age, 65 years). Of the 65 specimens, 59 (91%) were positive for HPV, and 62 (95%) expressed p16. The incidence of tonsillar cancer in the cohort demonstrated a 2-fold increase between 1990 and 2013; specifically, a 2.7-fold increase was observed in men whilst the female group exhibited only a small increase. These findings demonstrate a strong association between p16 expression and HPV infection in tonsillar malignancies. The incidence of HPV-positive tonsillar cancer has increased in recent years, even in sparsely populated regions, as demonstrated in northern Sweden.

  • 7.
    Ofverman, Charlotte
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    CASE SERIES OF PATIENTS WITH LEIOMYOSARCOMA OF THE UTERUS TREATED WITH TRABECTEDIN IN NORTHERN SWEDEN2016In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, no Supplement 3, p. 1046-1046, article id IGCS-0142Article in journal (Refereed)
  • 8.
    Rahman, Mozibur
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Ming-De
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Neurosteroid modulation of recombinant rat alpha5beta2gamma2L and alpha1beta2gamma2L GABA(A) receptors in Xenopus oocyte.2006In: Eur J Pharmacol, ISSN 0014-2999, Vol. 547, no 1-3, p. 37-44Article in journal (Refereed)
  • 9.
    Stefansson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Oda, Husam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    LRIG protein expression and HPV prevalence in vulvar cancer patients in northern Sweden2015In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, no 9, p. 684-684Article in journal (Other academic)
  • 10.
    Stefansson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Oda, Husam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG1‑2 and LMO7 immunoreactivity in vulvar squamous cell carcinoma: association with prognosis in relation to HPV‑DNA and p16INK4a status2019In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 42, no 1, p. 142-150Article in journal (Refereed)
    Abstract [en]

    The present study was conducted to investigate the possible prognostic value of molecular markers LRIG1‑2 and LIM domain 7 protein (LMO7) in vulvar squamous cell carcinoma (VSCC) and their possible correlation to human papilloma virus (HPV)‑ and p16INK4a‑status of the tumors. Patients diagnosed with VSCC at the University Hospital of Umeå, Sweden, during the years 1990‑2013 were selected. Tumor blocks were retrieved from tissue archives and clinical data were collected from the records of patients. HPV‑PCR analysis, HPV genotyping and immunohistochemistry were performed. In total, 112 patients were included. Forty percent of the tumors were HPV‑positive, 27% were p16INK4a‑positive and 23% were positive for both HPV and p16INK4a (considered HPV‑driven). HPV‑positivity and p16INK4a‑positivity were associated with prolonged disease‑free survival (DFS) in Kaplan‑Meier survival analysis. Leucine‑rich repeats and immunoglobulin‑like domains 1 (LRIG1) immunoreactivity was not significantly associated with survival. High leucine‑rich repeats and immunoglobulin‑like domains 2 (LRIG2) immunoreactivity was associated with a prolonged overall survival (OS) (P=0.001). By analyzing HPV‑negative cases only, it was determined that high LRIG2 immunoreactivity was associated with both favorable OS (P=0.008) and DFS (P=0.031). LRIG2 immunoreactivity was also an independent prognostic factor in multivariate analysis of OS (P=0.002, HR=0.41; 95% CI, 0.24‑0.71). High immunoreactivity with LMO7‑1250 antibody was associated with survival benefits in the whole cohort (OS; P=0.011) although DFS was only prolonged in HPV‑negative and not HPV‑driven tumors (P=0.038 and 0.042, respectively). The present study indicated that LRIG2 and LMO7 may be useful prognostic markers in VSCC, particularly for patients without HPV‑driven tumors or with advanced tumors at diagnosis. In contrast to earlier observations regarding other types of squamous cell carcinoma, LRIG1 was not a significant prognostic factor in VSCC.

  • 11.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
    Progesterone metabolites: learning, tolerance, antagonism & metabolism2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Progesterone metabolites as allopregnanolone, isoallopregnanolone and tetrahydrodeoxy-corticosterone (THDOC) are increased in the luteal phase of the menstrual cycle, throughout pregnancy and during stress. Allopregnanolone and THDOC are neurosteroids with 3α-hydroxy, 5α-configurations and positive modulating effect on the GABAA receptor. They have similar properties and effect, and share the same binding sites on the GABAA receptor. Isoallopregnanolone has a 3β-hydroxy, 5α-configuration and a diverse effect as a proposed antagonist to both allopregnanolone and THDOC. Neurosteroids are thought to exert their effect predominantly at extrasynaptic GABAA receptors, containing for example α4- or α5-subunits. Such receptors are involved in the tonic response. Different subunits have diverse distribution pattern in the brain and are involved in different functions. The α5-subunit, mainly expressed in the hippocampus, is involved in learning, while α4 is more widespread and involved in e.g. anxiety and anaesthesia.

    The aim of the present thesis was to contribute to the knowledge about selected progesterone metabolites and their effects on learning and tolerance development, as well as their metabolism. Also basic characteristics between different α-subunits of the GABAA receptor were evaluated.

    The thesis shows that the effect of bicuculline and pentobarbital is not dependent on the α-subunit isoform of the GABAA receptor expressed in oocytes. Acute tolerance developed after allopregnanolone-induced anaesthesia with a decrease at both mRNA and protein levels of the GABAA receptor α4-subunit in the thalamus VPM nucleus. A negative correlation between the α4 mRNA and the increased dose of allopregnanolone needed to maintain the anaesthesia level was also shown. In addition, allopregnanolone induces a learning impairment in the Morris water maze test, when high concentrations of allopregnanolone are present in the brain. This impairment is not possible to reverse by isoallopregnanolone. In α5β3γ2L-transfected HEK-293 cells THDOC induces a baseline shift of its own and also potentiate the GABA-current. Neither of those THDOC effects can be inhibited by isoallopregnanolone. Instead isoallopregnanolone shows an agonistic effect on the THDOC-potentiation of the GABA-response. The main allopregnanolone metabolites identified, 5α-DHP and isoallopregnanolone, as well as allopregnanolone itself are mainly localized to the brain after an i.v. injection. After an isoallopregnanolone injection there is a more even distribution of the given steroid and the metabolites between plasma and brain. There is an epimerisation between isoallopregnanolone and allopregnanolone and vice versa.

    In conclusion, the present thesis shows that the α4-subunit in the thalamus VPM nucleus is likely to be involved in the acute tolerance development against allopregnanolone and that allopregnanolone-induced learning impairment is likely to be hippocampus dependent. The lack of antagonistic effect of isoallopregnanolone on the THDOC-induced α5β3γ2L-GABAA response, together with epimerisation of isoallopregnanolone to allopregnanolone, could explain why isoallopregnanolone does not work as an antagonist to the allopregnanolone-induced learning impairment in a hippocampus dependent learning task.

  • 12.
    Öfverman, Charlotte
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hill, Martin
    Institute of Endocrinology, Nároni trída 8, CZ 116 94 Prague, Czech Republic.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Neurosteroid metabolism: identification of allopregnanolone and isoallopregnanolone metabolites in rat brain and plasmaManuscript (preprint) (Other academic)
    Abstract [en]

    Metabolism of progesterone produces steroids that by themselves have other functional properties than the hormone. The most prominent metabolite, allopregnanolone (3α-OH-5α-pregnane-20-one), has a strong GABAA receptor agonistic activity. Isoallopregnanolone (3β-OH-5α-pregnane-20-one) is also formed from progesterone; this allopregnanolone epimer can in certain situations function as an antagonist to effects induced by allopregnanolone.

    This study was designed to further evaluate the metabolism of allopregnanolone and isoallopregnanolone in the rat. This was done by intravenous injections of either steroid and analyses of selected possible metabolites within the brain as well as in plasma, eight minutes after the injection. Analyses were performed with GC-MS.

    It was found that the main metabolites accumulated after the allopregnanolone treatment was the precursor 5α-dihydroprogesterone, followed by isoallopregnanolone. The injected allopregnanolone, as well as the two major metabolites formed, were mainly present in the brain. When isoallopregnanolone was injected, the main metabolites formed were allopregnanolone and 6α-hydroxylated isoallopregnanolone, followed by the precursor 5α-dihydroprogesterone. Interestingly, the metabolites formed after isoallopregnanolone injections were more evenly distributed between the analyzed brain areas and the plasma. After both treatments a high proportion of conjugation (typically around 50%), was in plasma found for both the injected and the produced steroids.

    With the high amounts of metabolites found in the brain, there might be a high converting capacity within the brain for these kinds of steroids. This suggests that interchange between the studied epimers is of physiological nature. One may then speculate that the brain uses the conversion between allopregnanolone and isoallopregnanolone to regulate the GABAergic inhibition. If this is the case, a dysregulation of this metabolism might cause symptoms and/or CNS disorders. 

  • 13.
    Öfverman, Charlotte
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hill, Martin
    Institute of Endocrinology, Nároní trída 8, CZ 116 94, Prague, Czech Republic.
    Lundgren, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    The progesterone metabolite isoallopregnanolone is a subunit-selective antagonist of the GABA-A receptorManuscript (preprint) (Other academic)
    Abstract [en]

     Allopregnanolone is a progesterone metabolite that can negatively affect learning and induce anaesthesia in rats. It also impairs episodic memory in women. Allopregnanolone levels are elevated during the luteal phase of the menstrual cycle, during pregnancy, and during stress. Allopregnanolone is a strong positive modulator of the GABAA receptor. The subunit composition of the GABAA receptor is of importance for effects of modulators, and GABAA receptors including the α5-subunit are of significance for learning, while receptors with other subunits are involved in e.g. anesthesia. Isoallopregnanolone, a natural 3β-epimer of allopregnanolone, has been shown to antagonize allopregnanolone-induced anesthesia in rats.

    We tried to block the allopregnanolone-induced impairment of learning in rats in the Morris water maze test, using isoallopregnanolone (4–32 mg/kg). We also determined steroid concentrations in blood and brain tissue, and with whole-cell patch clamp we studied the effects of isoallopregnanolone and tetrahydrodeoxycorticosterone (a neurosteroid similar to allopregnanolone) on HEK-293 cells expressing the human α5β2γ2L GABAA receptor.

    Isoallopregnanolone did not block the negative effects of allopregnanolone (2 mg/kg) in the Morris water maze test. Our presumed antagonist actually had an agonistic effect on the tetrahydrodeoxycorticosterone-mediated potentiation of the GABA effect on the α5β2γ2L GABAA receptor. The baseline shift induced by tetrahydrodeoxycorticosterone alone was not reversed by isoallopregnanolone. A bidirectional epimerisation between allopregnanolone and isoallopregnanolone was also identified in the rat.

    The lack of antagonistic effect at the α5β2γ2L GABAA receptor together with the epimerisation of isoallopregnanolone to allopregnanolone would probably explain the lack of effect of our proposed antagonist on the allopregnanolone-induced impairment of learning 

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