17beta-Estradiol attenuates blood-brain barrier disruption induced by cerebral ischemia-reperfusion injury in female rats.
Disruption of blood-brain barrier (BBB), mediated through matrix metalloproteinases (MMPs), is a critical event during cerebral ischemia. While neuroprotective effects of estrogens have been well established in ischemic stroke models, the effects of estrogens on BBB integrity remain to be elucidated. In the present study, we determined effects of 17beta-estradiol (E2) on BBB disruption induced by transient focal cerebral ischemia and its effects on MMP2 and MMP9 activation. Transient cerebral ischemia was induced by middle cerebral artery (MCA) occlusion for 1 h followed by reperfusion in ovariectomized rats. E2 (100 microg/kg) or vehicle was administered 2 h before MCA occlusion. BBB integrity was determined by fluorescent detection of extravasated Evans blue. In separate experiments, effect of E2 on MMP2 and MMP9 expression and activation was determined by immunoblot and MMPs activity assay. E2 treatment prevented more than 50% and 30% of BBB disruption in the ischemic cortex and subcortex at 4 h after reperfusion, respectively. MMP2 and MMP9 expression was elevated at 2 h and peaked at 4 h after reperfusion in the ischemic cortex, which was markedly reduced by E2 treatment. E2 treatment also attenuated the increase of MMPs activity induced by ischemia-reperfusion injury. In conclusion, estrogens could attenuate BBB disruption induced by transient cerebral ischemia, by inhibition of MMP2 and MMP9 activation. Our results suggest an important role of estrogens as multiple targeting protectants against ischemic stroke on cellular as well as vascular components of central nervous system.
Liu
Ran
R
Department of Pharmacology and Neuroscience, University of North Texas, Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
Wen
Yi
Y
Perez
Evelyn
E
Wang
Xiaofei
X
Day
Arthur L
AL
Simpkins
James W
JW
Yang
Shao-Hua
SH
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy / Q000201:enzymology; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology
D018696:Neuroprotective Agents; D004958:Estradiol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9