Estrogen receptor-mediated resveratrol actions on blood-brain barrier of ovariectomized mice

Neurobiol Aging. 2015 Feb;36(2):993-1006. doi: 10.1016/j.neurobiolaging.2014.09.024. Epub 2014 Oct 13.


To test whether resveratrol provides benefits via estrogen receptors (ERs) in the blood-brain barrier of estrogen-deficient females, ovariectomized mice were treated with resveratrol then were subjected to transient middle cerebral artery occlusion (MCAO). Compared with vehicle treatment, resveratrol reduced infarct volume and neurologic deficits after MCAO. Basal tight junction (TJ) protein levels in the brain were increased by resveratrol. After MCAO, blood-brain barrier breakdown reduced levels of TJ proteins, and induction of HIF-1α and VEGF were attenuated by resveratrol. These effects were reversed by the ERs antagonist, ICI182,780. In mouse brain, endothelial cells (bEnd.3) exposed to hypoxia, resveratrol treatment protected the cells against cytotoxicity, increases of paracellular permeability and changes in levels of TJ protein and HIF-1α/VEGF proteins. These effects were reversed by ICI182,780 but not by specific ERα or ERβ antagonists, indicating nonspecific ER mediated effects. Altogether, these results showed that neuroprotective effects of resveratrol in ovariectomized mice were mediated by ERs and associated with tightening of blood-brain barrier, suggesting that resveratrol can be an alternative to estrogens to protect the brains of estrogen-deficient females against ischemic insult.

Keywords: Blood-brain barrier permeability; Estrogen receptors; Ischemic stroke; Ovariectomy; Resveratrol; Tight junction protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects*
  • Brain / cytology
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Female
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / prevention & control
  • Mice, Inbred C57BL
  • Neuroprotective Agents*
  • Ovariectomy*
  • Postmenopause
  • Receptors, Estrogen / metabolism*
  • Receptors, Estrogen / physiology*
  • Resveratrol
  • Stilbenes / pharmacology*
  • Stilbenes / therapeutic use*
  • Tight Junction Proteins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neuroprotective Agents
  • Receptors, Estrogen
  • Stilbenes
  • Tight Junction Proteins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Resveratrol