Jin-Min Guo1, He Shu1, Lei Wang2, Jian-Jiang Xu1, Xue-Cai Niu3, Li Zhang1. 1. Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China. 2. Department of Orthopaedics, Jinan Military General Hospital, Jinan, Shandong, China. 3. Department of Radiotheropy, The Forth Hospital of Jinan City, Jinan, Shandong, China.
Abstract
AIMS: 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. CONCLUSION: Our data support that estrogen protects against ischemic stroke through preventing neuron death via the SIRT1-dependent AMPK pathway.
AIMS: 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 ischemiarats, 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. CONCLUSION: Our data support that estrogen protects against ischemic stroke through preventing neuron death via the SIRT1-dependent AMPK pathway.
Authors: Christina L Bell; Andrea LaCroix; Kamal Masaki; Erinn M Hade; Todd Manini; W Jerry Mysiw; Jess David Curb; Sylvia Wassertheil-Smoller Journal: J Am Geriatr Soc Date: 2013-07-19 Impact factor: 5.562
Authors: JoAnn E Manson; Rowan T Chlebowski; Marcia L Stefanick; Aaron K Aragaki; Jacques E Rossouw; Ross L Prentice; Garnet Anderson; Barbara V Howard; Cynthia A Thomson; Andrea Z LaCroix; Jean Wactawski-Wende; Rebecca D Jackson; Marian Limacher; Karen L Margolis; Sylvia Wassertheil-Smoller; Shirley A Beresford; Jane A Cauley; Charles B Eaton; Margery Gass; Judith Hsia; Karen C Johnson; Charles Kooperberg; Lewis H Kuller; Cora E Lewis; Simin Liu; Lisa W Martin; Judith K Ockene; Mary Jo O'Sullivan; Lynda H Powell; Michael S Simon; Linda Van Horn; Mara Z Vitolins; Robert B Wallace Journal: JAMA Date: 2013-10-02 Impact factor: 56.272