Neurogenesis and Functional Recovery After Stroke Enhanced by Estrogen

Article Outline

• Disclosures
• Objective
• Design
• Setting
• Participants
• Interventions
• Main Outcome Measures
• Results
• Conclusions
• Copyright

Keywords: Rehabilitation, Stroke, Neurogenesis, Estrogens

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Disclosures 

M. Yuan, None.

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Objective 

It is well documented that estrogen provides neuroprotection from numerous types of brain pathology in animal models. This study is to investigate the role of estrogen in neurogenesis and functional recovery after acute experimental stroke.

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Design 

Randomized controlled preclinical study.

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Setting 

Laboratory at a University Health Center.

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Participants 

C57BL/6 wild type (WT) male and female mice (n = 8/group). Female mice deficient in Aromatase (ARKO), Estrogen Receptor (ER)α(ERKO) and ERβ (BERKO)(n = 8/group).

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Interventions 

Male and female mice were subjected to reversible 90 minutes middle cerebral artery occlusion. Females were ovariectomized 7 days prior to stroke. Both males and females were given implants of physiological doses of 17-β-estradiol (E2) or oil vehicle. Animals were injected with the cell proliferation marker BrdU 1 week after ischemia. Mice were allowed to survive for 2 or 6 weeks.

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Main Outcome Measures 

Brains were analyzed for BrdU, a newborn neuron marker Doublecortin (DCX) and a mature neuron marker NeuN, with immunohistochemistry and confocal microscopy. Infarction was quantified with cresyl violet. Functional recovery was evaluated with cylinder test at the 2nd day and every week after stroke.

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Results 

Significant numbers of newborn neurons (BrdU+/DCX+) were observed in the subventricular zone (SVZ) and dentate gyrus (DG) 2 weeks after stroke in the WT mice. E2 treated group showed a significant increase of BrdU+/DCX+ cells compared with the control in the DG (49.6 ± 5.7 vs 21.3 ± 5.0 in male, 46.6 ± 6.8 vs 25.6 ± 6.9 in female, P < .01). Similar result was obtained in the SVZ. Mature neurons (BrdU+/NeuN+) were present in the DG 6 weeks after stroke and were significantly increased in number in the E2 group (55.5 ± 6.5 vs 25.4 ± 4.8 in male, 59.4 ± 6.1 vs 26.3 ± 4.3 in female, P < .01). Estrogen treatment reduced infarct damage and also significantly accelerated functional recovery on the cylinder test. All gene knock out mice (ARCO, ERKO and BERKO) study revealed a significantly reduced BrdU+/DCX+ cells in the DG and SVZ at 2 weeks after stroke, compared with the WT control.

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Conclusions 

Estrogen is an important contributor to stroke-induced neurogenesis and functional recovery. Estrogen-enhanced neurogenesis may be mediated by estrogen receptor alpha and beta.