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Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis
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.ORCID iD: 0000-0001-8813-0384
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.
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.
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.
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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. Vol. 6
National Category
Clinical Medicine Microbiology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-123892DOI: 10.1038/srep21086ISI: 000370034300001OAI: oai:DiVA.org:liu-123892DiVA: diva2:893622
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: 2016-03-09Bibliographically approved
In thesis
1. Challenges in experimental stroke research: The 17β-estradiol example
Open this publication in new window or tab >>Challenges in experimental stroke research: The 17β-estradiol example
2016 (English)Doctoral 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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1504
National Category
Basic Medicine Neurosciences
Identifiers
urn:nbn:se:liu:diva-123893 (URN)10.3384/diss.diva-123893 (DOI)978-91-7685-852-3 (print) (ISBN)
Public defence
2016-02-05, Berzeliussalen, Ingång 65, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-01-13 Created: 2016-01-13 Last updated: 2016-01-15Bibliographically approved

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Ingberg, EdvinDock, HuaTheodorsson, ElvarTheodorsson, AnnetteStröm, Jakob O
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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Clinical ChemistryDivision of Microbiology and Molecular MedicineDepartment of Neurosurgery
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