title: Lose dose genistein inhibits glucocorticoid receptor and ischemic brain injury in female rats.
abstract: Although acute bolus of genistein treatment has been shown to protect against neuronal damage in experimental brain injury animal models, chronic continuous low dose treatment of genistein on ischemic brain injury has not been well elucidated. In the present study, female rats were received either pure genistein (0.1mg/kg/day via osmotic minipumps) or placebo at the time of ovariectomy, and transient forebrain ischemia was induced 7days later. Results demonstrated that genistein treatment for 14days significantly improved ischemic neuronal survival in hippocampal CA1 region of ovariectomized rats. Glucocorticoid receptor (GR) is a member of the adrenal steroid hormone receptor, which is highly expressed in the rat hippocampus. Activation of the GR plays a critical role in the neuronal stress responses, including ischemic brain damage. This study therefore examined the potential mechanisms by which genistein regulates GR signaling, including the protein distribution and receptor activation in hippocampus following ischemic reperfusion (I/R). Results showed that GR expression in the ovariectomized rats was excessively increased both in neurons (I/R 6h) and activated microglial cells (I/R 7d) in hippocampal CA1 region. Genistein treatment significantly attenuated GR induction and the enhanced GR nuclear translocation and DNA-binding capacity. The effects of genistein on the GR levels was accompanied with decreased blood plasma levels of corticosterone (primary glucocorticoid in rodents) and coupled to an E3 ubiquitin ligase Mdm2 targeted proteasomal degradation of GR, because genistein treatment could enhance the GR-Mdm2 interaction and the ubiquitination level of GR protein. In addition, our results indicated that genistein markedly prevented the excessive activation of microglia in CA1 sector. These results demonstrate the neuroprotective action of chronic low dose genistein replacement against ischemic brain damage, and a potential mechanism associated with the inhibition of both neuronal and microglial GR signaling following ischemic stress.
authors: School of Kinesiology, Shanghai University of Sport, 588 Qingyuan Huan Road, Shanghai 200438, China. Electronic address: rfshi@sus.edu.cn.
authors: Rengfei
authors: R
authors: Shi
authors: School of Kinesiology, Shanghai University of Sport, 588 Qingyuan Huan Road, Shanghai 200438, China.
authors: Shunli
authors: S
authors: Wang
authors: School of Kinesiology, Shanghai University of Sport, 588 Qingyuan Huan Road, Shanghai 200438, China.
authors: Xiang
authors: X
authors: Qi
authors: School of Kinesiology, Shanghai University of Sport, 588 Qingyuan Huan Road, Shanghai 200438, China.
authors: Si
authors: S
authors: Chen
authors: School of Kinesiology, Shanghai University of Sport, 588 Qingyuan Huan Road, Shanghai 200438, China.
authors: Peijie
authors: P
authors: Chen
authors: School of Kinesiology, Shanghai University of Sport, 588 Qingyuan Huan Road, Shanghai 200438, China. Electronic address: qgzhang@ustc.edu.
authors: Quanguang
authors: Q
authors: Zhang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D019833:Genistein
keywords: Brain injury; Genistein replacement; Glucocorticoid receptor; Hippocampus; Microglia; Osmotic pump; Transient forebrain ischemia