Estrogen Receptor (ER)-α36 Is Involved in Estrogen- and Tamoxifen-Induced Neuroprotective Effects in Ischemic Stroke Models.
The neuroprotection by estrogen (E2) and tamoxifen is well documented in experimental stroke models; however, the exact mechanism is unclear. A membrane-based estrogen receptor, ER-α36, has been identified. Postmenopausal-levels of E2 act through ER-α36 to induce osteoclast apoptosis due to a prolonged activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) signaling. We hypothesized that ER-α36 may play a role in the neuroprotective activities of estrogen and tamoxifen. Here, we studied ER-α36 expression in the brain, as well as its neuroprotective effects against oxygen and glucose deprivation (OGD) in PC12 cells. We found that ER-α36 was expressed in both rat and human brain. In addition, OGD-induced cell death was prevented by l nmol/L 17β-estradiol (E2β). E2β activates the MAPK/ERK signaling pathway in PC12 cells under basal and OGD conditions by interacting with ER-α36 and also induces ER-α36 expression. Low-dose of tamoxifen up-regulated ER-α36 expression and enhanced neuronal survival in an ovariectomized ischemic stroke model. Furthermore, low-dose of tamoxifen enhanced neuroprotective effects by modulating activates or suppress ER-α36. Our results thus demonstrated that ER-α36 is involved in neuroprotective activities mediated by both estrogen and tamoxifen.
College of Life Science, Liaoning Normal University, Dalian 116081, China; Liaoning Key Laboratories of Biotechnology and Molecular Drug Research and Development, Dalian, 116081, China.
Wei
W
Zou
College of Life Science, Liaoning Normal University, Dalian 116081, China.
Chen
C
Fang
Regenerative Medicine Centre, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Xiaofei
X
Ji
College of Life Science, Liaoning Normal University, Dalian 116081, China.
Xiaofeng
X
Liang
College of Life Science, Liaoning Normal University, Dalian 116081, China.
Yang
Y
Liu
Regenerative Medicine Centre, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; College of Life Science, Liaoning Normal University, Dalian 116081, China.
Chao
C
Han
College of Life Science, Liaoning Normal University, Dalian 116081, China.
Liang
L
Huang
College of Life Science, Liaoning Normal University, Dalian 116081, China.
Qiqi
Q
Zhang
College of Life Science, Liaoning Normal University, Dalian 116081, China; Liaoning Key Laboratories of Biotechnology and Molecular Drug Research and Development, Dalian, 116081, China.
Hongyan
H
Li
College of Life Science, Liaoning Normal University, Dalian 116081, China; Liaoning Key Laboratories of Biotechnology and Molecular Drug Research and Development, Dalian, 116081, China.
Yejun
Y
Zhang
Department of Cardiology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Jinqiu
J
Liu
Regenerative Medicine Centre, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Jing
J
Liu
D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000627:therapeutic use*; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016716:PC12 Cells; D051381:Rats; D020521:Stroke / Q000378:metabolism* / Q000517:prevention & control; D013629:Tamoxifen / Q000627:therapeutic use*
D047628:Estrogen Receptor alpha; D004967:Estrogens; D018696:Neuroprotective Agents; C000601334:estrogen receptor alpha 36, human; D013629:Tamoxifen