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  • 1.
    Ingberg, Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Challenges in experimental stroke research: The 17β-estradiol example2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ischemic stroke causes millions of deaths around the world each year, and surviving patients often suffer from long-term disability. Hundreds of promising drug candidates have been identified in animal models, but the clinical trials have repeatedly failed. Lack of methodological quality in the animal studies, e.g. low statistical power as a result of small group sizes in combination with high outcome variability and high mortality, has been suggested to in part explain the lack of translational success. In the meta-analytical Papers II and Paper V, we therefore investigated how method parameters impact infarct size variation and mortality in rodent stroke studies. These findings can help researchers to optimize their animal models or to more exactly predict variability and mortality given a certain experimental setup.

    The relation between ischemic stroke and estrogens is complex. Premenopausal women have a lower risk of stroke than men of the same age, suggesting that female sex hormones provide protection against cerebrovascular events. The idea of a beneficial effect on the brain of estrogens was also supported by epidemiological studies showing that estrogens given as postmenopausal hormone replacement therapy decreased the risk of stroke. However, subsequent clinical trials reported the opposite, an increased risk. Interestingly, discrepancies exist also in the animal stroke literature. The majority of the rodent studies on the effects of estrogens have shown protection, but there are also several examples of increased damage. Based on experimental results and a meta-analysis, it was hypothesized that differences in hormone administration methods and their resulting plasma concentrations of estrogens might explain the previous discordant animal findings. Paper I investigated the commonly used methods for 17β-estradiol administration and found that the popular slow-release pellets produced high and unpredictable serum concentrations. A novel method with 17β-estradiol administered orally in Nutella® was also evaluated with promising results. Paper III extracted data regarding methodological choices from all previously published estrogen-stroke studies, and showed through metaanalysis that slow-release pellets are more prone to render estrogens damaging. Finally, Paper IV tested whether estrogens could both exert neuroprotection and promote detrimental effects merely depending on dose and irrespective of the administration route. Surprisingly, and in contrast to the hypothesis, a significant negative correlation was found between 17β-estradiol dose group and infarct size meaning that the higher the dose, the smaller the infarcts.

    In summary, this thesis does not confirm the hypothesis of dose-related neuroprotective vs neurodamaging effects of estrogens on ischemic stroke. If high estrogen doses/plasma concentrations per se can cause increased stroke damage, such a phenomenon is not very robust, and seems to depend on tight dose ranges and/or other experimental circumstances. Although not directly applicable to the clinical situation, hopefully in a long-term perspective these findings may contribute in elucidating when estrogens are beneficial and when they are harmful. Further, it adds to the growing literature on how the quality of experimental stroke research can be increased to try to overcome translational difficulties.

    List of papers
    1. Methods for long-term 17β-estradiol administration to mice
    Open this publication in new window or tab >>Methods for long-term 17β-estradiol administration to mice
    2012 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 188-193Article in journal (Refereed) Published
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within – except on one occasion – the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

    Place, publisher, year, edition, pages
    Elsevier, 2012
    Keywords
    Estradiol; Slow-release pellets; Silastic capsule; Per os; Uterine weight
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:liu:diva-107100 (URN)10.1016/j.ygcen.2011.11.014 (DOI)000299065800022 ()22137913 (PubMedID)2-s2.0-84855192470 (Scopus ID)
    Available from: 2014-06-05 Created: 2014-06-05 Last updated: 2019-12-20Bibliographically approved
    2. Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis
    Open this publication in new window or tab >>Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis
    2013 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 14, no 41Article in journal (Refereed) Published
    Abstract [en]

    Background

    Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains.

    Methods

    We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability.

    Results

    The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method.

    Conclusions

    The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality.

    Place, publisher, year, edition, pages
    BioMed Central, 2013
    Keywords
    Brain infarction, Middle cerebral artery occlusion, Rats, Methods, Mortality, Variability
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-93981 (URN)10.1186/1471-2202-14-41 (DOI)000318616000001 ()23548160 (PubMedID)
    Note

    Funding Agencies|County Council of Ostergotland, Sweden||

    Available from: 2013-06-13 Created: 2013-06-13 Last updated: 2019-12-20Bibliographically approved
    3. Impact of methodology on estrogens’ effects on cerebral ischemia in rats: an updated meta-analysis
    Open this publication in new window or tab >>Impact of methodology on estrogens’ effects on cerebral ischemia in rats: an updated meta-analysis
    2014 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, no 22Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for.

    RESULTS:

    The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats.

    CONCLUSIONS:

    We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.

    Place, publisher, year, edition, pages
    BioMed Central, 2014
    Keywords
    Cerebral ischemia; Estradiol; Estrogens; Meta-analysis; Rats; Stroke
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-106875 (URN)10.1186/1471-2202-15-22 (DOI)000334885400001 ()24495535 (PubMedID)
    Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2019-12-20Bibliographically approved
    4. Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    Open this publication in new window or tab >>Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    2016 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n=40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modifi ed sticky tape test was performed after 24 h and the rats were subsequently sacrifi ced for infarct size measurements. In contrast to our hypothesis, a signifi cant negative correlation between 17β-estradiol dose and infarct size was found (p=0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the fi ndings indicate that the higher the dose of 17β-estradiol, the smaller the infarct.

    National Category
    Clinical Medicine Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-123890 (URN)
    Available from: 2016-01-13 Created: 2016-01-13 Last updated: 2019-12-20Bibliographically approved
    5. Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Open this publication in new window or tab >>Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Show others...
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Article in journal (Refereed) Published
    Abstract [en]

    Although hundreds of promising substances have been tested in clinical trials, thrombolysis currently remains the only specifi c pharmacological treatment for ischemic stroke. Poor quality, e.g. low statistical power, in the preclinical studies has been suggested to play an important role in these failures. Therefore, it would be attractive to use animal models optimized to minimize unnecessary mortality and outcome variability, or at least to be able to power studies more exactly by predicting variability and mortality given a certain experimental setup. The possible combinations of methodological parameters are innumerous, and an experimental comparison of them all is therefore not feasible. As an alternative approach, we extracted data from 334 experimental mouse stroke articles and, using a hypothesis-driven meta-analysis, investigated the method parameters’ impact on infarct size variability and mortality. The use of Swiss and C57BL6 mice as well as permanent occlusion of the middle cerebral artery rendered the lowest variability of the infarct size while the emboli methods increased variability. The use of Swiss mice increased mortality. Our study offers guidance for researchers striving to optimize mouse stroke models.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2016
    National Category
    Clinical Medicine Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-123892 (URN)10.1038/srep21086 (DOI)000370034300001 ()
    Note

    Funding agencies:  County Council of Ostergotland, Sweden

    Vid tiden för disputation förelåg publikationen endast som manuskript

    Available from: 2016-01-13 Created: 2016-01-13 Last updated: 2019-12-20Bibliographically approved
  • 2.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Orebro Univ, Sweden.
    Dock, Hua
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ström, Jakob O.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Orebro Univ, Sweden.
    Effect of laser Doppler flowmetry and occlusion time on outcome variability and mortality in rat middle cerebral artery occlusion: inconclusive results2018In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 19, article id 24Article in journal (Refereed)
    Abstract [en]

    Background: Stroke is among the leading causes of death and disability. Although intense research efforts have provided promising treatment options in animals, most clinical trials in humans have failed and the therapeutic options are few. Several factors have been suggested to explain this translational difficulty, particularly concerning methodology and study design. Consistent infarcts and low mortality might be desirable in some, but not all, studies. Here, we aimed to investigate whether the use of laser Doppler flowmetry (LDF) and the occlusion time (60 vs. 45 min) affected outcome variability and mortality in a rat stroke model. Eighty ovariectomized female Wistar rats were subjected to ischemic stroke using intraluminal filament middle cerebral artery occlusion with or without LDF and with occlusion times of 45 or 60 min. Outcome was evaluated by triphenyl tetrazolium chloride staining of brain slices to measure infarct size and a modified sticky tape test. Results: Neither LDF nor occlusion times of 45 versus 60 min significantly affected mortality, outcome variability or outcome severity. Conclusions: Due to the unexpectedly high mortality and variability the statistical power was very low and thus the results were inconclusive.

  • 3.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Dock, Hua
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ström, Jakob O
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Vårdvetenskapligt Forskningscentrum/Centre for Health Sciences, Örebro University Hospital, Region Örebro Län, Örebro, Sweden / School of Health and Medical Sciences, Örebro University, Örebro, Sweden..
    Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Article in journal (Refereed)
    Abstract [en]

    Although hundreds of promising substances have been tested in clinical trials, thrombolysis currently remains the only specifi c pharmacological treatment for ischemic stroke. Poor quality, e.g. low statistical power, in the preclinical studies has been suggested to play an important role in these failures. Therefore, it would be attractive to use animal models optimized to minimize unnecessary mortality and outcome variability, or at least to be able to power studies more exactly by predicting variability and mortality given a certain experimental setup. The possible combinations of methodological parameters are innumerous, and an experimental comparison of them all is therefore not feasible. As an alternative approach, we extracted data from 334 experimental mouse stroke articles and, using a hypothesis-driven meta-analysis, investigated the method parameters’ impact on infarct size variability and mortality. The use of Swiss and C57BL6 mice as well as permanent occlusion of the middle cerebral artery rendered the lowest variability of the infarct size while the emboli methods increased variability. The use of Swiss mice increased mortality. Our study offers guidance for researchers striving to optimize mouse stroke models.

  • 4.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics.
    Gudjonsdottir, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. County Council Örebro, Sweden; University of Örebro, Sweden.
    Elevated body swing test after focal cerebral ischemia in rodents: methodological considerations2015In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 16, no 50Article in journal (Refereed)
    Abstract [en]

    Background: The elevated body swing test (EBST) is a behavioral test used to evaluate experimental stroke in rodents. The basic idea is that when the animal is suspended vertically by the tail, it will swing its head laterally to the left or right depending on lesion side. In a previous study from our lab using the EBST after middle cerebral artery occlusion (MCAo), rats swung contralateral to the infarct day 1 post-MCAo, but ipsilateral day 3 post-MCAo. This shift was unexpected and prompted us to perform the present study. First, the literature was systematically reviewed to elucidate whether a similar shift had been noticed before, and if consensus existed regarding swing direction. Secondly, an experiment was conducted to systematically investigate the suggested behavior. Eighty-three adult male and female Sprague-Dawley rats were subjected to MCAo or sham surgery and the EBST was performed up to 7 days after the lesion. Results: Both experimentally and through systematic literature review, the present study shows that the direction of biased swing activity in the EBST for rodents after cerebral ischemia can differ and even shift over time in some situations. The EBST curve for females was significantly different from that of males after the same occlusion time (p = 0.023). Conclusions: This study highlights the importance of adequate reporting of behavioral tests for lateralization and it is concluded that the EBST cannot be recommended as a test for motor asymmetry after MCAo in rats.

  • 5.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob O
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Methods for long-term 17β-estradiol administration to mice2012In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 188-193Article in journal (Refereed)
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within – except on one occasion – the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

  • 6.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. veÖrebro University Hospital, Sweden; Unirsity of Örebro, Sweden.
    Effects of high and low 17 beta-estradiol doses on focal cerebral ischemia in rats2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 20228Article in journal (Refereed)
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17 beta-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n = 40 per group) were randomized into three groups, subcutaneously administered different doses of 17 beta-estradiol and subjected to transient middle cerebral artery occlusion. The modified sticky tape test was performed after 24 h and the rats were subsequently sacrificed for infarct size measurements. In contrast to our hypothesis, a significant negative correlation between 17 beta-estradiol dose and infarct size was found (p = 0.018). Thus, no support was found for the hypothesis that 17 beta-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the findings indicate that the higher the dose of 17 beta-estradiol, the smaller the infarct.

  • 7.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ström, Jakob O
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Vårdvetenskapligt Forskningscentrum/Centre for Health Sciences, Örebro University Hospital, Region Örebro Län, Örebro, Sweden / School of Health and Medical Sciences, Örebro University, Örebro, Sweden..
    Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats2016Manuscript (preprint) (Other academic)
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n=40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modifi ed sticky tape test was performed after 24 h and the rats were subsequently sacrifi ced for infarct size measurements. In contrast to our hypothesis, a signifi cant negative correlation between 17β-estradiol dose and infarct size was found (p=0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the fi ndings indicate that the higher the dose of 17β-estradiol, the smaller the infarct.

  • 8.
    Ström, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Örebro University Hospital, Sweden.
    Ingberg, Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Impact of methodology on estrogens’ effects on cerebral ischemia in rats: an updated meta-analysis2014In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, no 22Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for.

    RESULTS:

    The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats.

    CONCLUSIONS:

    We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.

  • 9.
    Ström, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Ingberg, Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis2013In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 14, no 41Article in journal (Refereed)
    Abstract [en]

    Background

    Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains.

    Methods

    We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability.

    Results

    The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method.

    Conclusions

    The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality.

  • 10.
    Ström, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Ingberg, Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Effects of high and low 17 beta-estradiol doses on focal cerebral ischemia: negative results2013In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3Article in journal (Refereed)
    Abstract [en]

    The reasons why some animal studies indicate that estrogens increase focal cerebral ischemic damage while others show estrogen-induced neuroprotection has hitherto not been fully elucidated. Recent evidence indicates that discrepancies in hormone administration paradigms, resulting in highly different serum hormone concentrations, may account for the dichotomy. The current study aimed to test this hypothesis. Sixty ovariectomized female rats were randomized into three groups differing in 17 beta-estradiol regimens, and transient focal cerebral ischemia was subsequently induced. All animals were subjected to a small functional testing battery, and three days after MCAo they were sacrificed for infarct size assessment. Infarct sizes did not differ between groups, however clear discrepancies were seen in body weight and feeding behavior. In comparison to sham-operated animals, ovariectomized rats rapidly increased in body weight, whereas the opposite was seen in rats receiving 17beta-estradiol. The weight gain in the ovariectomized rats was paralleled by an increased food intake.

  • 11.
    Ström, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Ingberg, Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Effects of high and low 17β-estradiol doses on cerebral ischemiaManuscript (preprint) (Other academic)
    Abstract [en]

    INTRODUCTION: Estrogens’ effects on cerebral ischemia have during the last two decades been the subject of intense research efforts. Notwithstanding this, the reasons that some studies indicate that estrogens are damaging while others show estrogen-induced neuroprotection has hitherto not been fully elucidated. Recent evidence indicates that discrepancies in hormone administration paradigms, resulting in highly different serum hormone concentrations, may account for this dichotomy. The current study was designed to test this  ypothesis.

    METHODS: Sixty ovariectomized female rats were randomized into three groups differing in subsequent 17β-estradiol regimen (vehicle, low dose and high dose respectively). Following two weeks of treatment, focal cerebral ischemia was induced via an intraluminal filament middle cerebral artery occlusion (MCAo) method. All animals were subjected to a small functional testing battery, and three days after MCAo they were sacrificed for infarct size assessment.

    RESULTS AND DISCUSSION: The hormone administration regimens significantly affected animal weights and feeding behavior, but infarct sizes did not differ between groups. Further, random intra-group variations in infarct size were too large to allow negative conclusions to be drawn. The large variation was possibly a consequence of too large occluding filament diameter in combination with that the animals were allowed to wake up during ongoing MCAo. After correcting the large variation, the hypothesis needs to be addressed anew.

  • 12.
    Ström, Jakob O
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ingberg, Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Druvefors, Emma
    Ryhov County Hospital, County Council of Jönköping, Sweden.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    The female menstrual cycle does not influence testosterone concentrations in male partners2012In: Journal of Negative Results in Biomedicine, ISSN 1477-5751, E-ISSN 1477-5751, Vol. 11, no 1Article in journal (Refereed)
    Abstract [en]

    Background

    The time of ovulation has since long been believed to be concealed to male heterosexual partners. Recent studies have, however, called for revision of this notion. For example, male testosterone concentrations have been shown to increase in response to olfactory ovulation cues, which could be biologically relevant by increasing sexual drive and aggressiveness. However, this phenomenon has not previously been investigated in real-life human settings. We therefore thought it of interest to test the hypothesis that males' salivary testosterone concentrations are influenced by phases of their female partners' menstrual cycle; expecting a testosterone peak at ovulation.

    Methods

    Thirty young, healthy, heterosexual couples were recruited. During the course of 30-40 days, the women registered menses and ovulation, while the men registered sexual activity, physical exercise, alcohol intake and illness (confounders), and obtained daily saliva samples for testosterone measurements. All data, including the registered confounders, were subjected to multiple regression analysis.

    Results

    In contrast to the hypothesis, the ovulation did not affect the testosterone levels, and the resulting testosterone profile during the menstrual cycle was on the average flat. The specific main hypothesis, that male testosterone levels on the day of ovulation would be higher than day 4 of the cycle, was clearly contradicted by a type II error(β)-analysis (< 14.3% difference in normalized testosterone concentration; β = 0.05).

    Conclusions

    Even though an ovulation-related salivary testosterone peak was observed in individual cases, no significant effect was found on a group level.

  • 13.
    Ström, Jakob O
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ingberg, Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Isaksson, Ida-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ovariectomy and 17β-estradiol replacement in rats and mice: a visual demonstration2012In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 64, p. 4013-Article in journal (Refereed)
    Abstract [en]

    Estrogens are a family of female sexual hormones with an exceptionally wide spectrum of effects. When rats and mice are used in estrogen research they are commonly ovariectomized in order to ablate the rapidly cycling hormone production, replacing the 17β-estradiol exogenously. There is, however, lack of consensus regarding how the hormone should be administered to obtain physiological serum concentrations This is crucial since the 17β-estradiol level/administration method profoundly influences the experimental results1-3. We have in a series of studies characterized the different modes of 17β-estradiol administration, finding that subcutaneous silastic capsules and per-oral nut-cream Nutella are superior to commercially available slow-release pellets (produced by the company Innovative Research of America) and daily injections in terms of producing physiological serum concentrations of 17β-estradiol4-6. Amongst the advantages of the nut-cream method, that previously has been used for buprenorphine administration7, is that when used for estrogen administration it resembles peroral hormone replacement therapy and is non-invasive. The subcutaneous silastic capsules are convenient and produce the most stable serum concentrations. This video article contains step-by-step demonstrations of ovariectomy and 17β-estradiol hormone replacement by silastic capsules and peroral Nutella in rats and mice, followed by a discussion of important aspects of the administration procedures.

1 - 13 of 13
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