TY - JOUR
T1 - Estrogen receptor-mediated resveratrol actions on blood-brain barrier of ovariectomized mice
AU - Shin, Jin A.
AU - Oh, Seikwan
AU - Ahn, Jung Hyuck
AU - Park, Eun Mi
N1 - Funding Information:
This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIP) ( 2010-0011353 , 2011-0015923 , and 2012R1A5A2A32671867 ).
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - 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.
AB - 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.
KW - Blood-brain barrier permeability
KW - Estrogen receptors
KW - Ischemic stroke
KW - Ovariectomy
KW - Resveratrol
KW - Tight junction protein
UR - http://www.scopus.com/inward/record.url?scp=84922801083&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2014.09.024
DO - 10.1016/j.neurobiolaging.2014.09.024
M3 - Article
C2 - 25448605
AN - SCOPUS:84922801083
SN - 0197-4580
VL - 36
SP - 993
EP - 1006
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 2
ER -