Different methods for administering 17β-estradiol to ovariectomized rats result in opposite effects on ischemic brain damage

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Abstract

Background: Numerous stroke studies have controversially shown estrogens to be either neuroprotective or neurodamaging. The discordant results observed in rat brain ischemia models may be a consequence of discrepancies in estrogen administration modes resulting in plasma concentration profiles far from those intended. To test this hypothesis we reproduced in detail and extended an earlier study from our lab using a different mode of 17β-estradiol administration; home-made silastic capsules instead of commercial slow-release 17β-estradiol pellets. Four groups of female rats (n = 12) were ovariectomized and administered 17β-estradiol or placebo via silastic capsules. All animals underwent MCAo fourteen days after ovariectomy and were sacrificed three days later.Results: In contrast to our earlier results using the commercial pellets, the group receiving 17β-estradiol during the entire experiment had significantly smaller lesions than the group receiving placebo (mean ± SEM: 3.85 ± 0.70% versus 7.15 ± 0.27% of total slice area, respectively; p = 0.015). No significant neuroprotection was found when the 17β-estradiol was administered only during the two weeks before or the three days immediately after MCAo.Conclusions: The results indicate that different estrogen treatment regimens result in diametrically different effects on cerebral ischemia. Thus the effects of estrogens on ischemic damage seem to be concentration-related, with a biphasic, or even more complex, dose-response relation. These findings have implications for the design of animal experiments and also have a bearing on the estrogen doses used for peri-menopausal hormone replacement therapy. © 2010 Strom et al; licensee BioMed Central Ltd.

Figures

  • Figure 1 Study flow-chart. All animals were ovariectomized day 0 of the experiment, and at the same time Gr.P/P and Gr.P/E received placebo implants, while Gr.E/E and Gr.E/P received estrogen implants. Day 14 of the experiment, all animals underwent 60 minutes of MCAo. During the anesthesia, blood samples were drawn and the implants were replaced with new ones. Gr.P/P and Gr.E/P received placebo implants, while Gr.E/E and Gr.P/E received estrogen implants. On day 17 of the experiment, all animals were sacrificed, trunk blood collected and brains harvested for analysis.
  • Figure 2 Serum estradiol concentrations depends on administration mode. The three most commonly-used methods for administrating 17b-estradiol to rats were tested in a previous study [23]: slow-release pellets (0.25 mg 60 day-release pellets, 0.10 mg 90 day-release pellets) and silastic capsules (silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with 20 mm columns of 180 μg 17b-estradiol/mL sesame oil). Blood samples were obtained at days 2, 7, 14, 21, 28, 35 and 42 after administration, and hormone levels were analyzed. As can be observed in the graph, silastic capsules produced 17b-estradiol concentrations that were within the physiological range for at least 4 weeks, while the pellets resulted in early supraphysiological peaks followed by a substantial decrease.
  • Figure 3 Total ischemic brain lesion. The mean ischemic lesion area calculated from all slices in each experimental group. Gr.P/P had significantly larger lesions than Gr.E/E (p = 0.015).
  • Figure 4 Ischemic lesion in individual slices. Mean areas of ischemic lesions in individual slices are presented. The lesions were largest at bregma and smallest in bregma -8 mm in all experimental groups.
  • Table 1 Physiological parameters in rats subjected to transient MCA occlusion
  • Table 2 Concentrations of 17b-estradiol (mean ± SEM pg/mL)
  • Table 3 Methodological comparison of previous and present study

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Strom, J. O., Theodorsson, E., Holm, L., & Theodorsson, A. (2010). Different methods for administering 17β-estradiol to ovariectomized rats result in opposite effects on ischemic brain damage. BMC Neuroscience, 11. https://doi.org/10.1186/1471-2202-11-39

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