| 1. |
- Björn, Inger, 1953-, et al.
(författare)
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Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy
- 2003
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 88:5, s. 2026-2030
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have indicated that the addition of progestinsduring sequential hormonal replacement therapy (HRT)causes negative mood and physical symptoms. History of premenstrualsyndrome, type of progestin, and dose of progestinhave thus far been shown to influence the progestin-inducedadverse mood symptoms during HRT.The aim of this study was to compare adverse mood effectsof two different doses of estradiol, in combination with a progestin,during postmenopausal HRT. Twenty-eight perimenopausalwomen were included in this randomized, doubleblind,crossover study comparing 2- or 3-mg continuousestradiol, with an addition of 10 mg medroxyprogesteroneacetate on d 17–28 during each treatment cycle. The mainoutcome measures were mood and physical symptoms kept ona daily rating scale. Together with the progestin, the higherdose of estrogen caused significantly more negative moodsymptoms than the lower dose. Tension, irritability, and depressedmood were all significantly augmented during theprogestin phase of cycles with 3mg estradiol (P<0.001). Physicalsymptoms also increased during the progestin phase of3-mg estradiol cycles (P<0.001), whereas positive mood symptomswere less affected. The only positive mood that changedwith estrogen dose was friendliness, which decreased duringthe progestin phase of high estradiol cycles compared withcycles with lower estradiol (P < 0.05).Our conclusion is that an increase of the estrogen doseaccentuates negativemoodand physical symptoms during theprogestin phase of sequential hormonal therapy.
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| 2. |
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| 3. |
- Pettersson-Pablo, Paul, 1986-, et al.
(författare)
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Body fat percentage and CRP correlates with a composite score of vascular risk markers in healthy, young adults : The Lifestyle, Biomarkers, and Atherosclerosis (LBA) study
- 2020
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Ingår i: BMC Cardiovascular Disorders. - : BioMed Central. - 1471-2261 .- 1471-2261. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Identification of early signs of atherosclerosis in young adults have the potential to guide early interventions to prevent later cardiovascular disease. We therefore analyzed measures of vascular structure and function and biomarkers of cardiovascular risk in a sample of young healthy adults.METHODS: Pulse-wave velocity (PWV), carotid-intima media thickness (cIMT) and augmentation index (AIX) were measured in 834 healthy non-smokers (ages 18.0-25.9). Emphasis was put on discriminating between individuals having a vascular structure and function associated with a higher or lower risk, and cluster analysis algorithms were employed to assign the subjects into groups based on these vascular measurements. In addition, a vascular status score (VSS) was calculated by summarizing the results according to quintiles of the vascular measurements. The associations between VSS and cardiovascular biomarkers were examined by regression analyses.RESULTS: The cluster analyses did not yield sufficiently distinct clustering (groups of individuals that could be categorized unequivocally as having either a vascular structure and function associated with a higher or lower CVD risk). VSS proved a better classificatory variable. The associations between VSS and biomarkers of cardiovascular risk were analyzed by univariable and multivariable regressions. Only body fat percentage and C-reactive protein (CRP) were independently associated with VSS.CONCLUSIONS: A VSS calculation, which integrates PWV, cIMT, and AIX measurements is better suited for cardiovascular risk evaluation in young adults than cluster analyses. The independent associations of VSS with body fat percentage and CRP highlight the decisive role of adiposity and systemic inflammation in early atherosclerotic progression and suggests a subordinate role of insulin and lipid metabolism in this age span.
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| 4. |
- Ahangari, Alebtekin, et al.
(författare)
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Acute intermittent porphyria symptoms during the menstrual cycle
- 2015
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Ingår i: Internal medicine journal (Print). - : Wiley. - 1444-0903 .- 1445-5994. ; 45:7, s. 725-731
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Tidskriftsartikel (refereegranskat)abstract
- Background: Acute intermittent porphyria (AIP), a life-threatening form of the disease, is accompanied by several pain, mental and physical symptoms.Aims: In this study, we evaluated the cyclicity of AIP and premenstrual syndrome (PMS) symptoms in 32 women with DNA-diagnosed AIP during their menstrual cycles, in northern Sweden.Methods: The cyclicity of AIP symptoms and differences in them between the follicularand luteal phases, and the cyclicity of each symptom in each individual woman indifferent phases of her menstrual cycle were analysed with a prospective daily ratingquestionnaire. PMS symptoms were also evaluated in the patients on a daily rating scale.Results: Of the 32 women, 30 showed significant cyclicity in at least one AIP or PMS symptom (P < 0.05–0.001). Back pain (10/32) was the most frequent AIP pain symptomand sweet craving (10/15) was the most frequent PMS symptom. Pelvic pain (F = 4.823,P = 0.036), irritability (F = 7.399, P = 0.011), cheerfulness (F = 5.563, P = 0.025), sexualdesire (F = 8.298, P = 0.007), friendliness (F = 6.157, P = 0.019), breast tenderness (F =21.888, P = 0.000) and abdominal swelling (F = 16.982, P = 0.000) showed significantcyclicity. Pelvic pain and abdominal swelling (rs= 0.337, P < 0.001) showed the strongest correlation. The age of women with latent AIP was strongly correlated with abdominal swelling during the luteal phase (rs= 0.493, P < 0.01).Conclusion: Our results suggest that the symptoms of AIP patients change during their menstrual cycles.
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| 5. |
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| 6. |
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| 7. |
- Andersson, Christer, et al.
(författare)
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Acute intermittent porphyria in women : clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden
- 2003
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 254:2, s. 176-183
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To describe the clinical expression of acute intermittent porphyria (AIP) in women, their use of exogenous sex hormones, and the effects on AIP. DESIGN: A retrospective population-based study. SUBJECTS: All women aged > or =18 years (n = 190) with DNA-diagnosed AIP in northern Sweden. RESULTS: A total of 166 women (87%) participated; 91 (55%) had manifest AIP. Severe attacks were reported by 82%; 39% reported recurrent premenstrual AIP attacks and 22% reported chronic AIP symptoms. Oral hormonal contraceptives had been used by 58% of all these women and by 50 with manifest AIP (57%). Twelve women (24%) associated oral contraceptives as precipitating AIP attacks; in nine cases their first attack. One woman experienced relief from AIP symptoms. On commencing their treatment, 72% of the women with manifest AIP had not yet suffered their first attack. Twenty-two women (25%) aged > or =45 years had used hormonal replacement therapy (HRT) at menopause to remedy climacteric symptoms (the percutaneous route was most frequently used); no AIP attack was precipitated. HRT to remedy vaginal dryness was used by 26 women (28%) aged > or =45 years without triggering an AIP attack. Miscarriages were more frequent in women with manifest AIP (50%) than in the latent group (30%, P = 0.014). CONCLUSIONS: About half of the women with AIP had used oral hormonal contraceptives. As 25% of women with manifest AIP reported attacks associated with such drugs, caution must still be recommended. Menopausal HRT only rarely affected the disorder. Miscarriage was more common amongst women with manifest AIP.
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| 8. |
- Andersson, Christer, 1945-, et al.
(författare)
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Atypical attack of acute intermittent porphyria : paresis but not abdominal pain
- 2002
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 252:3, s. 265-270
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Tidskriftsartikel (refereegranskat)abstract
- We report a case of acute intermittent porphyria (AIP) in a 45-year-old woman. Her first attack occurred at the age of 38. Because of escalating cyclical premenstrual attacks, the following 2 years, depletion of the endogenous sex hormone was considered as haeme arginate treatment proved insufficient. Gonadotropin releasing hormone agonist treatment with low-dose oestradiol add back was quite successful initially but was abandoned after 18 months when progesterone add back precipitated a severe attack. Following hysterectomy and oophorectomy at age 42 and oestradiol add back, a remarkable monthly regularity of attacks ensured periodically but with milder symptoms. Two years after surgery, preceded by six attack-free months, a puzzling symptom-shift occurred, from abdominal pain, back and thigh pain during the attacks, to solely severe distal extensor paresis in the arms. Haeme arginate treatment interrupted the progress of the paresis almost immediately and motor function improved considerably up to the 9-month follow-up. Electrophysiological examination revealed only motor neuropathy, consistent with axonal degeneration. Subsequently the symptoms changed yet again, to sensory disturbances with numbness and dysesthesia as the primary expression followed by rather mild abdominal pain. However, cyclical attacks occurred, despite absence of endogenous ovarial hormone production, possibly attributable to impaired oestrogen metabolism in the liver, or adrenal oestrogen production. Treatment comprising oophorectomy, low-dose oestradiol add back and haeme arginate infusion for 2 days on the appearance of early AIP symptoms is now quite successful affording improvement in life quality.
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| 9. |
- Andréen, Lotta, 1961-
(författare)
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Allopregnanolone and mood : studies of postmenopausal women during treatment with progesterone
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction. Allopregnanolone and pregnanolone (neuroactive metabolites of progesterone) act as positive modulators of the GABAA receptor system which is the major inhibitory system in CNS. Contradictory results on the effect of GABAA receptor modulators are reported. Beneficial properties such as anaesthesia, sedation, and anxiolysis are reported as well as adverse, anxiogenic and aggressive effects. It has been suggested that GABAA receptor agonists have bimodal effects. Low concentrations increase an adverse, anxiogenic effect, whereas higher concentrations show beneficial, calming properties. Aims. To investigate if progesterone treatment induces adverse mood in postmenopausal women and if the severity in mood symptoms is related to progesterone, allopregnanolone or pregnanolone serum concentrations. To evaluate differences in steroid concentrations induced by different doses and routes of administration of progesterone. Methods. Two randomised, placebo-controlled, double-blind crossover studies of postmenopausal women were performed. Subjects were treated with estradiol continuously. Different doses of progesterone, given vaginally or orally, were added sequentially during the last 14 days of each treatment cycle. Daily symptom ratings were kept using a validated rating scale. Blood samples for progesterone, allopregnanolone and pregnanolone analyses were collected during each treatment cycle. A study regarding the pharmacokinetics after ingestion of low-dose oral progesterone was conducted with postmenopausal women. Blood samples for the analyses of progesterone, allopregnanolone and pregnanolone were collected and pharmacokinetic parameters were calculated. Results. Certain postmenopausal women on sequential HT with vaginal and oral progesterone experience mood deterioration during the progesterone phase while on a low dose of progesterone but not on higher doses or the placebo. Negative mood symptoms occurred when the serum concentration of allopregnanolone was similar to endogenous luteal phase levels, whereas lower and higher concentrations had no effect on mood. Pharmacokinetic analyses show that low-dose oral progesterone can be used as a prodrug to allopregnanolone when the aim is to achieve physiological concentrations of allopregnanolone. Conclusions. A bimodal association between allopregnanolone concentration and adverse mood is observed in postmenopausal women treated with progesterone. The addition of low-dose progesterone to estradiol induces adverse mood in postmenopausal women, whereas higher doses and placebo have no mood-deteriorating effect.
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Andréen, Lotta, et al.
(författare)
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Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators
- 2009
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 34:8, s. 1121-1132
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Tidskriftsartikel (refereegranskat)abstract
- Certain women experience negative mood symptoms as a result of progesterone during the luteal phase of the menstrual cycle, progestagens in hormonal contraceptives, or the addition of progesterone or progestagens in sequential hormone therapy (HT). This phenomenon is believed to be mediated via the action of the progesterone metabolites on the GABA(A) system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABA(A) receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABA(A) receptor modulators have shown contradictory results; although human and animal studies have revealed beneficial properties such as anaesthesia, sedation, anticonvulsant effects, and anxiolytic effects, recent reports have also indicated adverse effects such as anxiety, irritability, and aggression. It has actually been suggested that several GABA(A) receptor modulators, including allopregnanolone, have biphasic effects, in that low concentrations increase an adverse, anxiogenic effect whereas higher concentrations decrease this effect and show beneficial, calming properties. The allopregnanolone increase during the luteal phase in fertile women, as well as during the addition of progesterone in HT, has been shown to induce adverse mood in women. The severity of these mood symptoms is related to the allopregnanolone serum concentrations in a manner similar to an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. It has also been shown that progesterone/allopregnanolone treatment in women increases the activity in the amygdala (as measured with functional magnetic resonance imaging) in a similar way to the changes seen during anxiety reactions. However, it is evident that only certain women experience adverse mood during progesterone or GABA(A) receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABA(A) receptor sensitivity and GABA concentrations that are related to the severity of the condition. These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA(A) receptor. CONCLUSION: Progesterone and progestagens induce negative mood, most probably via their GABA(A) receptor active metabolites. In postmenopausal women treated with progesterone and animals treated with allopregnanolone, there is a bimodal association between serum allopregnanolone concentration and adverse mood, resembling an inverted U-shaped curve. In humans, the maximal effective concentration of allopregnanolone for producing negative mood is within the range of physiological luteal phase serum concentrations.
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| 15. |
- Appelblad, Patrik, et al.
(författare)
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Determination of C-21 ketosteroids in serum using trifluoromethanesulfonic acid catalyzed precolumn dansylation and 1,1’-oxalyldiimidazole postcolumn peroxyoxalate chemiluminescence detection
- 1998
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Ingår i: Analytical Chemistry. - Washington : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 70:23, s. 5002-5009
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Tidskriftsartikel (refereegranskat)abstract
- A new procedure for the quantitation of C-21 ketosteroids using trifluoromethanesulfonic acid-catalyzed precolumn dansylation and coupled column liquid chromatographic separation, followed by postcolumn 1,1‘-oxalyldiimidazole peroxyoxalate chemiluminescence detection is presented. In the simultaneous optimization of chromatographic resolution and chemiluminescence intensity, a coupled column chromatographic system and a stopped-flow system were used. An eluent containing 20 mM phosphate buffer at pH 6.7 accomplished an efficient separation of 3α-hydroxy-5β-pregnan-20-one from a mixture containing 10 C-21 ketosteroids. Phosphate buffer also proved to be the most advantageous, among the six buffers tested, for sensitive detection. Experimental design and multivariate data analysis were used to characterize and optimize the postcolumn reaction chemistry in the chromatographic system. A valid full factorial design with excellent predictability showed that the flow rates for both 1,1‘-oxalyldiimidazole and hydrogen peroxide were the factors most strongly affecting the sensitivity of the system. The theoretical plate numbers were above 11 000 for all 10 dansylated ketosteroids. The 3σ detection limit estimated from 3α-hydroxy-5β-pregnan-20-one calibration curve data was 1.6 pmol (n = 4, 125 μL injected) and spiked serum containing 0−74 pmol of this compound showed overall recoveries of 73 ± 9% (n = 12). Quantitation of 3α-hydroxy-5β-pregnan-20-one was finally carried out on 45 serum samples and the results compared to those from a radioimmunoassay (RIA) method. The data acquired with the procedure described in this work compare well with the results from RIA, which confirms the reliability of the new analytical procedure.
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| 16. |
- Appelblad, Patrik, et al.
(författare)
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Perfluorosulfonated Ionomer-Modified Polyethylene. A Material for Simultaneous Solid-Phase Enrichment and Enhanced Precolumn Dansylation of C-21 Ketosteroids in Human Serum
- 2001
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 73:15, s. 3701-8
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Tidskriftsartikel (refereegranskat)abstract
- A new derivatization procedure has been developed where solid-phase catalysis is utilized to facilitate the formation of hydrazones in precolumn labeling of keto-containing compounds. This procedure has been implemented on a solid-phase enrichment and enhanced derivatization (SPEED) device, prepared from porous polyethylene that has been coated with Nafion and dansylhydrazine. The SPEED devices have been optimized using experimental design and characterized for dansylation of C-21 ketosteroids by multivariate data analysis, using progesterone as the model compound. The reaction temperature and the molar ratio between the steroid and the derivatization reagent were found to be the factors most strongly affecting the reaction. Faster reaction kinetics were achieved when the molar ratio between dansylhydrazine and the steroid was increased. Mass spectroscopic analysis showed that the four derivative peaks eluting when derivatized progesterone was separated on an octadecyl silica stationary phase were due to the syn and anti mono- and bis(hydrazones) formed in the reaction. Using optimal reaction conditions, the derivatives mainly constitute the syn and anti conformers of bis-derivatives. In contrast to solution-based acid catalysis, the SPEED device was remarkably insensitive to water in the reaction mixture. A sample volume of 400 L was found to be the maximum, enabling sample enrichment prior derivatization. Using optimal experimental conditions, picomole amounts of ketosteroids could be derivatized in 10 min at room temperature. Analysis of spiked serum samples containing 0.4-2.0 nmol of progesterone showed overall recoveries of 52-63%. The corresponding 3 detection limit was 1.3 pmol (n = 4, 100 L injected), as estimated from calibration curve data.
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| 17. |
- Bannbers, Elin, 1984-, et al.
(författare)
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Prefrontal activity during response inhibition decreases over time in the postpartum period
- 2013
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328 .- 1872-7549. ; 241, s. 132-138
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Tidskriftsartikel (refereegranskat)abstract
- The postpartum period is characterized by complex hormonal changes, but human imaging studies in the postpartum period have thus far predominantly focused on the neural correlates of maternal behavior or postpartum depression, whereas longitudinal studies on neural correlates of cognitive function across the postpartum period in healthy women are lacking. The aim of this study was to longitudinally examine response inhibition, as a measure of executive function, during the postpartum period and its neural correlates in healthy postpartum women and non-postpartum controls. Thirteen healthy postpartum women underwent event-related functional magnetic resonance imaging while performing a Go/NoGo task. The first assessment was made within 48 h of delivery, and the second at 4-7 weeks postpartum. In addition, 13 healthy women examined twice during the menstrual cycle were included as non-postpartum controls. In postpartum women region of interest analyses revealed task-related decreased activations in the right inferior frontal gyrus, right anterior cingulate, and bilateral precentral gyri at the late postpartum assessment. Generally, postpartum women displayed lower activity during response inhibition in the bilateral inferior frontal gyri and precentral gyri compared to non-postpartum controls. No differences in performance on the Go/NoGo task were found between time-points or between groups. In conclusion, this study has discovered that brain activity in prefrontal areas during a response inhibition task decreases throughout the course of the first postpartum weeks and is lower than in non-postpartum controls. Further studies on the normal adaptive brain activity changes that occur during the postpartum period are warranted. (C) 2012 Elsevier B.V. All rights reserved.
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| 18. |
- Bengtsson, Sara, 1978-, et al.
(författare)
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Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models
- 2013
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Ingår i: Current Alzheimer Research. - : Bentham Science Publishers. - 1567-2050. ; 10:1, s. 38-47
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Aβ in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels. learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Ab in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels.
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| 19. |
- Bengtsson, Sara, 1978-, et al.
(författare)
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Chronic allopregnanolone elevation cause altered plaque production in Swe/PS1 mice
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Abstract. We have previously shown that chronic elevation of the neurosteroid allopregnanolone caused learning dysfunction and increased levels of soluble Aβ in the Swe/PS1 mouse model. The mechanism behind these findings is however unknown. We further investigated the brain tissue of these mice to identify any effects on congophilic plaque burden, Aβ42-specific plaque burden and synaptic function. We found a significant reduction in the average size of the congophilic core of neuritic plaques after chronic allopregnanolone treatment compared to vehicle. This seems to be caused by an altered plaque production, leading to more abundant, but smaller neuritic plaques. We may also have detected a decrease in the amount of synaptophysin, and thus synaptic function among the same mice. However, the long interval between the end of treatment and tissue collection possibly allowed time for recovery and only minor differences were noted. We found that the natural relationship between levels of insoluble Aβ, congophilic and Aβ42-specific plaque load was disrupted after chronically elevated allopregnanolone levels. Furthermore, the levels of syn-aptophysin and insoluble Aβ became more important in the relationship to learning and memory. The causality of these factors is still unknown and further studies are required to fully understand the effect of neurosteroids on AD development.
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| 20. |
- Bengtsson, Sara, 1978-, et al.
(författare)
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GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia?
- 2020
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Ingår i: Neurobiology of stress. - : Elsevier. - 2352-2895. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APa), it's role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APa given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APa impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APa depend on administration pattern and that chronic slightly increased APa exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APa and APa antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials.
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| 21. |
- Bengtsson, Sara K., et al.
(författare)
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Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice
- 2012
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 31:1, s. 71-84
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Tidskriftsartikel (refereegranskat)abstract
- The endogenous neurosteroid allopregnanolone alters neuronal excitability via modulation of the GABA(A) receptor and causes decreased neurotransmission. In Alzheimer's disease (AD), neurotransmission seems to alter the levels of toxic intracellular amyloid-beta (A beta) oligomers, which are implicated in AD pathogenesis and cause cognitive decline. Inhibition of synaptic activity has been shown to increase levels of intracellular A beta. Allopregnanolone at endogenous stress levels inhibits synaptic activity and could have similar effects. By using a transgenic A beta PP(Swe)PSEN1(Delta E9) mouse model for AD, we observed that chronic allopregnanolone treatment for three months with stress levels of allopregnanolone impaired learning in the Morris water maze. The learning impairment was seen one month after the end of treatment. Chronic allopregnanolone treatment also led to increased levels of soluble A beta in the brain, which could be a sign of advanced pathogenesis. Since the learning and memory of wild-type mice was not affected by the treatment, we propose that chronic allopregnanolone treatment accelerates the pathogenesis of AD. However, further studies are required in order to determine the underlying mechanism.
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| 22. |
- Bengtsson, Sara K. S., 1978-, et al.
(författare)
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Extra-synaptic GABAA receptor potentiation and neurosteroid-induced learning deficits are inhibited by GR3027, a GABAA modulating steroid antagonist
- 2023
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 13:10
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 23. |
- Bengtsson, Sara K. S., et al.
(författare)
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Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans
- 2015
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 52, s. 22-31
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Tidskriftsartikel (refereegranskat)abstract
- Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of gamma-amino-butyric acid (GABA) on the GABA type A (GABA(A)) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABA(A) receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP-induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner.
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| 24. |
- Bengtsson, Sara K S, et al.
(författare)
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Long-term continuous allopregnanolone elevation causes memory decline and hippocampus shrinkage, in female wild-type B6 mice
- 2016
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Ingår i: Hormones and Behavior. - : Elsevier BV. - 0018-506X .- 1095-6867. ; 78, s. 160-167
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Tidskriftsartikel (refereegranskat)abstract
- Chronic stress in various forms increases the risk for cognitive dysfunction, dementia and Alzheimer's disease. While the pathogenesis behind these findings is unknown, growing evidence suggests that chronic increase in neurosteroid levels, such as allopregnanolone, is part of the mechanism. We treated wild-type C57BL/6J mice with allopregnanolone for 5months, using osmotic pumps. This treatment led to moderately increased levels of allopregnanolone, equivalent to that of mild chronic stress. After an interval of no treatment for 1month, female mice showed impaired learning and memory function in the Morris water maze (MWM) in combination with diminished hippocampus weight and increased cerebellum weight, both correlating to MWM performance. Male mice showed a minor reduction in memory function and no differences in brain structure. We conclude that chronic allopregnanolone elevation can lead to cognitive dysfunction and negative brain alterations. We suggest that allopregnanolone could play a key role in the pathogenesis of stress-induced cognitive disturbances and perhaps dementia.
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- Bengtsson, Sara, 1978-
(författare)
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Stress steroids as accelerators of Alzheimer's disease. : Effects of chronically elevated levels of allopregnanolone in transgenic AD models.
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Alzheimer’s disease (AD) and dementia are devastating conditions not only for the affected patients but also for their families. The economical costs for the society are tremendous. Mid-life psychological stress, psychosocial stress and post-traumatic stress disorder cause cognitive dysfunction and lead to increased risk for dementia. However, the mechanisms behind stress-induced AD and dementia are not known. AD is characterized by solid amyloid plaques in the CNS. However, over the last decade it has been concluded that the levels of soluble beta-amyloid (Aβ) correlate to cognitive performance while plaques often do not. The soluble Aβ accumulate intracellularly and disturb the synaptic function. Interestingly, the levels of intracellular Aβ depend on neuronal activity. Previous studies have shown that decreased neuronal activity cause increased intracellular levels of Aβ and cognitive decline. Stress steroids produced in the brain, e.g. allopregnanolone, enhance the activity of the GABAergic system, i.e. the main inhibitory system of the brain. Consequently, allopregnanolone affects neuronal activity. Therefore, it is possible that elevated levels of allopregnanolone (due to e.g. stress) cause increased intracellular levels of Aβ. This could be a mechanism behind stress-induced AD. The purpose of this thesis was to investigate if elevation of allopregnanolone is a possible link in the mechanism behind stress-induced AD by investigating the effects of chronically elevated levels of allopregnanolone in transgenic mouse models for AD.Methods Swe/PS1 and Swe/Arc mice (transgenic models for AD) were treated chronically with elevated allopregnanolone levels, comparable to those at mild stress. After an interval of no treatment, the mice were tested for learning and memory performance in the Morris water maze. The brain tissue of the mice was then analyzed for disease markers, i.e. soluble and insoluble Aβ40 and Aβ42 using enzyme-linked immunosorbent assay, and amyloid plaques using immunohistochemistry and Congo red staining technique. The brain tissue was also analyzed for a marker of synaptic function, i.e. synaptophysin.Results Chronic treatment of allopregnanolone caused impaired learning performance in both the Swe/PS1 and the Swe/Arc mouse models. The Swe/PS1 mice had increased levels of soluble Aβ in both hippocampus and cortex. Interestingly, the levels of soluble Aβ were unchanged in the Swe/Arc mice. Three months of allopregnanolone treatment in the Swe/PS1 mouse model caused decreased plaque size, predominantly in hippocampus. It may be concluded that chronic allopregnanolone elevation caused smaller but more abundant congophilic plaques as both total plaque area and number of plaques were increased in mice with poor learning ability. Additional spots for accumulation of Aβ, predominantly the more toxic Aβ42, and thus additional starting points for plaque production could be a part of the mechanism behind stress-induced Alzheimer’s disease.Conclusions The conclusion of this thesis is that chronic elevation of allopregnanolon accelerated the development of Alzheimer’s disease in the Swe/PS1 and the Swe/Arc transgenic mouse models. Allopregnanolone may be an important link in the mechanism behind stress-induced AD. However, further studies are required to grasp the extent of its pathological influence.
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