The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17-oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway.

Autores de IIS La Fe

• María Consuelo Burguete López

  Autor

• Teresa Jover Mengual

  Autor

• Mikahela Andrea López Morales

  Autor

• Alicia Aliena Valero

  Autor

• Maria Jorques Gonzalez

  Autor

• Germán Torregrosa Bernabé

  Autor

• Enrique Alborch Domínguez

  Autor

• María Castelló Ruiz

  Autor

• Juan Bautista Salom Sanvalero

  Autor

Grupos

• Unidad Mixta de Investigación Cerebrovascular

  Leader

  Juan Bautista Salom Sanvalero

Abstract

Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40mgkg -1 streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (intraluminal thread technique, 60minutes) and assigned to one of three groups treated with either: vehicle, BZA (3mgkg -1 day -1 , i.p.) or 17-oestradiol (E 2 ) (100gkg -1 day -1 , i.p.). At 24hours post-ischaemia-reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of oestrogen receptors (ER)a, ER and G protein-coupled oestrogen receptor), and activity of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 and phosphoinositide 3-kinase/Akt pathways were analysed. At 24hours after the ischaemic insult, both BZA- and E 2 -treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size and decreased apoptotic cell death. Ischaemia-reperfusion induced a significant decrease in ERa and ER expression without affecting that of G protein-coupled oestrogen receptor, whereas BZA and E 2 reversed such a decrease. The ischaemic insult up-regulated the activity of both the MAPK/ERK1/2 and phosphoinositide 3-kinase/Akt pathways; BZA and E 2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The results of the present study lend further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E 2 with respect to improving diabetic ischaemic stroke outcome after successful reperfusion.

Keywords

• 17ß-oestradiol, apoptosis, bazedoxifene, diabetes, ischaemic stroke, selective oestrogen receptor modulators