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Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions
- Source :
- Proceedings of the National Academy of Sciences. 104:6013-6018
- Publication Year :
- 2007
- Publisher :
- Proceedings of the National Academy of Sciences, 2007.
-
Abstract
- Recent studies describing the seemingly contradictory actions of estrogens in ischemic stroke injury have led us to reevaluate the circumstances under which estrogen therapy (ET) provides benefits against cerebral stroke and decipher its mechanisms of action. One prominent feature that follows stroke injury is massive central and peripheral inflammatory responses. Evidence now suggests that postischemic inflammatory responses strongly contribute to the extent of brain injury, and 17β-estradiol (E 2 ) may protect the ischemic brain by exerting antiinflammatory actions. In an attempt to explain recently reported dichotomous effects of E 2 in stroke injury, we tested the hypothesis that an extended period of hypoestrogenicity both prevents E 2 from protecting the brain against ischemia and simultaneously suppresses its antiinflammatory actions. We report that E 2 exerts profound neuroprotective action when administered immediately upon ovariectomy, but not when administered after 10 weeks of hypoestrogenicity. Consistently, E 2 treatment given immediately at the time of ovariectomy attenuated central and peripheral production of proinflammatory cytokines after ischemic stroke. In contrast, E 2 did not suppress production of proinflammatory molecules when it was administered after 10 weeks postovariectomy. These results demonstrate that a prolonged period of hypoestrogenicity disrupts both neuroprotective and antiinflammatory actions of E 2 . Our findings may help to explain the results of the Women's Health initiative that reported no beneficial effect of ET against stroke because the majority of the subjects initiated ET after an extended period of hypoestrogenicity.
- Subjects :
- Vascular Endothelial Growth Factor A
medicine.medical_specialty
Time Factors
Ovariectomy
Anti-Inflammatory Agents
Ischemia
Down-Regulation
Inflammation
Pharmacology
Neuroprotection
Brain Ischemia
Proinflammatory cytokine
Brain ischemia
Mice
Internal medicine
Animals
Medicine
Interleukin 6
Stroke
Chemokine CCL2
Drug Implants
Multidisciplinary
Estradiol
biology
Interleukin-6
Tumor Necrosis Factor-alpha
business.industry
Estrogen Receptor alpha
Granulocyte-Macrophage Colony-Stimulating Factor
Biological Sciences
medicine.disease
Immunohistochemistry
Up-Regulation
Mice, Inbred C57BL
Neuroprotective Agents
Endocrinology
biology.protein
Female
medicine.symptom
business
Estrogen receptor alpha
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 104
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....88516ab1c89a45d7d639970736363c42