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  3. Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: A comparative study with 17 beta-estradiol

Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: A comparative study with 17 beta-estradiol

Fecha de publicación:

Autores de IIS La Fe

Grupos

Abstract

As the knowledge on the estrogenic system in the brain grows, the possibilities to modulate it in order to afford further neuroprotection in brain damaging disorders so do it. We have previously demonstrated the ability of the selective estrogen receptor modulator, bazedoxifene (BZA), to reduce experimental ischemic brain damage. The present study has been designed to gain insight into the molecular mechanisms involved in such a neuroprotective action by investigating: 1) stroke-induced apoptotic cell death; 2) expression of estrogen receptors (ER) ER alpha, ER beta and the G-protein coupled estrogen receptor (GPER); and 3) modulation of MAPK/ERK1/2 and PI3K/Akt signaling pathways. For comparison, a parallel study was done with 17 beta-estradiol (E2) treated animals. Male Wistar rats subject to transient right middle cerebral artery occlusion (tMCAO, intraluminal thread technique, 60 min), were distributed in vehicle-,BZA-(20.7 +/- 2.1 ng/mL in plasma) and E2- (45.6 +/- 7.8 pg/mL in plasma) treated groups. At 24 h from the onset of tMCAO, RT-PCR,Western blot and histochemical analysis were performed on brain tissue samples. Ischemia-reperfusion per se increased apoptosis as assessed by both caspase-3 activity and TUNEL-positive cell counts, which were reversed by both BZA and E2. ERa and ER beta expression, but not that of GPER, was reduced by the ischemic insult. BZA and E2 had different effects: while BZA increased both ER alpha and Ell beta expression, E2 increased ERa expression but did not change that of ER beta. Both MAPK/ERK1/2 and PI3K/Akt pathways were stimulated under ischemic conditions. While BZA strongly reduced the increased p-EFIK1/2 levels, E2 did not. Neither BZA nor E2 modified ischemia-induced increase in p-Akt levels. These results show that modulation of ERa and ER beta expression, as well as of the ERK1/2 signaling pathway accounts, at least in part, for the inhibitory effect of BZA on the stroke-induced apoptotic cell death. This lends mechanistic support to the consideration of BZA as a potential neuroprotective drug in acute ischemic stroke treatment.

Datos de la publicación

ISSN/ISSNe:
0960-0760, 1879-1220

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY  PERGAMON-ELSEVIER SCIENCE LTD

Tipo:
Article
Páginas:
296-304
Factor de Impacto:
1,431 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 26

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Keywords

  • Acute ischemic stroke; Apoptosis; Bazedoxifene; Estrogen; Estrogen receptors; Neuroprotection; Selective estrogen receptor modulators; Signaling pathways

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