The selective estrogen receptor modulator, bazedoxifene, reduces ischemic brain damage in male rat

Autores de IIS La Fe

• María Castelló Ruiz

  Autor

• Germán Torregrosa Bernabé

  Autor

• María Consuelo Burguete López

  Autor

• Francisco Javier Miranda Alonso

  Autor

• José María Centeno Guil

  Autor

• Mikahela Andrea López Morales

  Autor

• Teresa Gasull Dalmau

  Autor

• Enrique Alborch Domínguez

  Autor

Grupos

• Unidad Mixta de Investigación Cerebrovascular

  Leader

  Juan Bautista Salom Sanvalero

Abstract

While the estrogen treatment of stroke is under debate, selective estrogen receptor modulators (SERMs) arise as a promising alternative. We hypothesize that bazedoxifene (acetate, BZA), a third generation SERM approved for the treatment of postmenopausal osteoporosis, reduces ischemic brain damage in a rat model of transient focal cerebral ischemia. For comparative purposes, the neuroprotective effect of 17 beta-estradiol (E2) has also been assessed. Male Wistar rats underwent 60 min middle cerebral artery occlusion (intraluminal thread technique), and grouped according to treatment: vehicle-, E2- and BZA-treated rats. Optimal plasma concentrations of E2 (45.6 +/- 7.8 pg/ml) and BZA (20.7 +/- 2.1 ng/ml) were achieved 4h after onset of ischemia, and maintained until the end of the procedure (24 h). Neurofunctional score and volume of the damaged brain regions were the main end points. At 24 h after ischemia-reperfusion, neurofunctional examination of the animals did not show significant differences among the three experimental groups. By contrast, both E2- and BZA-treated groups showed significantly lower total infarct volumes, BZA acting mainly in the cortical region and E2 acting mainly at the subcortical level. Our results demonstrate that: (1) E2 at physiological plasma levels in female rats is neuroprotective in male rats when given at the acute stage of the ischemic challenge and (2) BZA at clinically relevant plasma levels mimics the neuroprotective action of E2 and could be, therefore, a candidate in stroke treatment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords

• Bazedoxifene; 17 beta-Estradiol; Ischemic stroke; Neuroprotection; Selective estrogen receptor modulators (SERMs)