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Estradiol and Progesterone Administration After pMCAO Stimulates the Neurological Recovery and Reduces the Detrimental Effect of Ischemia Mainly in Hippocampus

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Abstract

Epidemiological studies have suggested a differential response, males versus female, in stroke incidence and prognosis. These divergences in brain response after damage are based mostly on hormonal differences. To date, estradiol and progesterone administered independently have demonstrated neuroprotection after ischemia in animal models. Nonetheless, contradictory results were revealed using a combined administration. In order to evaluate the effects of combinatorial treatment administered after ischemia induction, we used two different approaches: in vivo and in vitro models. Male rats which underwent permanent middle cerebral artery occlusion were treated with a combination of estradiol/progesterone at 6, 24 and 48 h after injury and sacrificed at 54 h post-ischemia. The rat brains were evaluated for reactive gliosis, NeuN-positive neurons, levels of synapse-associated proteins and activity levels of PI3K/Akt/GSK3/β-catenin survival pathway. Also, primary cortical neurons were subjected to oxygen and glucose deprivation for 17 h and returned to a normal environment in the presence of estradiol or estradiol/progesterone. Cell viability was evaluated, and activity levels of the PI3K/Akt/GSK3/β-catenin pathway. Our results indicate that some beneficial effects of estradiol were abolished in the presence of progesterone, particularly in the cerebral cortex (core). However, the combinatorial treatment showed positive effects in the hippocampus.

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Acknowledgments

We are grateful to all members of Lab 206 at the Centro de Biología Molecular “Severo Ochoa” (CBM-SO) for thoughtful discussions during the preparation of this manuscript. This work was supported in part by grants from the CIBERNED (an initiative of ISCIII), the Plan Nacional DGCYT [SAF2012-39148-C03-01], and EU-FP7-2009-CT222887 and the Autonomous Government of Madrid (S20/BMD-2331). In addition CBM-SO was supported by an Institutional grant from the ‘Fundación Areces”.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departamento de Biología (Unidad Docente Fisiología Animal), Universidad Autónoma de Madrid, C/Darwin 2, 28049, Madrid, Spain

    Maria Jose Perez-Alvarez & Alvaro Alonso

  2. Centro de Biología Molecular “Severo Ochoa”. CSIC-UAM, C/ Nicolas Cabrera 1, 28049, Madrid, Spain

    Maria Jose Perez-Alvarez, Laura Mateos & Francisco Wandosell

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Maria Jose Perez-Alvarez & Francisco Wandosell

  4. Centro Nacional de Biotecnología. CSIC-CNB, C/ Darwin 3, 28049, Madrid, Spain

    Laura Mateos

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  1. Maria Jose Perez-Alvarez
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Correspondence to Francisco Wandosell.

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Perez-Alvarez, M.J., Mateos, L., Alonso, A. et al. Estradiol and Progesterone Administration After pMCAO Stimulates the Neurological Recovery and Reduces the Detrimental Effect of Ischemia Mainly in Hippocampus. Mol Neurobiol 52, 1690–1703 (2015). https://doi.org/10.1007/s12035-014-8963-7

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