title: SIRT1-dependent AMPK pathway in the protection of estrogen against ischemic brain injury.
abstract: OBJECTIVE
  Stroke is a major cause of mortality and disability, especially for postmenopausal women. In view of the protective action of estrogen, hormone therapy remains the only effective way to limit this risk. The objective of this study was to investigate the efficiency and underlying mechanisms of estrogen neuroprotection.
  
  
  METHODS
  Subcutaneous injection of 17β-estradiol in rats after ovariectomy (OVX) was used to manipulate estrogen level and explore the effects of estrogen in cerebral ischemic damage both in vivo and in vitro. Silent mating type information regulation 2 homolog 1 (SIRT1) knockout mice and adenosine monophosphate (AMP)-activated kinase (AMPK) inhibitor Compound C were also used to investigate the underlying pathway of estrogen.
  
  
  RESULTS
  Estrogen deficiency induced by OVX aggravated brain infarction in experimentally induced cerebral ischemia rats, whereas estrogen pretreatment reduced ischemia-induced cerebral injuries. Neurons of estrogen deficiency models were susceptible to apoptosis under oxygen-glucose deprivation (OGD). In contrast, neurons with estrogen-supplemented serum exhibited restored resistance to cell apoptosis. In OGD neurons, estrogen promoted AMPK activation through estrogen receptor α, and neuroprotection of estrogen was prevented by AMPK inhibition. Estrogen increased SIRT1 expression and activation, and estrogen-induced AMPK activation disappeared in SIRT1 knockout neurons. Moreover, estrogen-induced neuroprotection was abolished in SIRT1 knockout mice and AMPK-inhibited rats.
  
  
  CONCLUSIONS
  Our data support that estrogen protects against ischemic stroke through preventing neuron death via the SIRT1-dependent AMPK pathway.
authors.affiliation: Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: Jin-Min
authors.identifier: http://orcid.org/0000-0001-5737-7384
authors.initials: JM
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: He
authors.initials: H
authors.lastname: Shu
authors.affiliation: Department of Orthopaedics, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: Jian-Jiang
authors.initials: JJ
authors.lastname: Xu
authors.affiliation: Department of Radiotheropy, The Forth Hospital of Jinan City, Jinan, Shandong, China.
authors.forename: Xue-Cai
authors.initials: XC
authors.lastname: Niu
authors.affiliation: Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use*; D004967:Estrogens / Q000097:blood; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D004958:Estradiol; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: 
  AMPK
  ; SIRT1; estrogen; ischemic stroke