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Critical Care Medicine:
doi: 10.1097/CCM.0b013e3182657560
Neurologic Critical Care

G-protein coupled estrogen receptor 1 mediated estrogenic neuroprotection against spinal cord injury*

Hu, Rong MD, PhD; Sun, Haodong MD; Zhang, Qian BPharm, MBA; Chen, Jingyu MD; Wu, Nan MD, PhD; Meng, Hui MD, PhD; Cui, Gaoyu MD, PhD; Hu, Shengli MD, PhD; Li, Fei MD, PhD; Lin, Jiangkai MD, PhD; Wan, Qi MD, PhD; Feng, Hua MD, PhD

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Abstract

Objective: What underlies the protection of estrogen against spinal cord injury remains largely unclear. Here, we investigated the expression pattern of a new estrogen receptor, G-protein coupled estrogen receptor 1 in the spinal cord and its role in estrogenic protection against spinal cord injury.

Design and Settings: Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital.

Subjects: Male Sprague–Dawley rats.

Interventions: The animals subjected to spinal cord injury were divided into six groups and given vehicle solution, 17β-estradiol, or G-protein coupled estrogen receptor 1 agonist G-1 at 15 mins and 24 hrs postinjury, or given nuclear estrogen receptor antagonist ICI 182,780 at 1 hr before spinal cord injury followed by 17β-estradiol administration at 15 mins and 24 hrs postinjury, or given G-protein coupled estrogen receptor 1 specific antisense or random control oligonucleotide at 4 days before spinal cord injury followed by 17β-estradiol administration at 15 mins and 24 hrs postinjury.

Measurements: Male Sprague–Dawley rats were subjected to spinal cord injury using a weight-drop injury approach. Immunohistochemical assays were used to observe the distribution and cell-type expression pattern of G-protein coupled estrogen receptor 1. The terminal deoxynucleotidyl transferase dUTP nick-end labeling-staining assay and behavior tests were employed to assess the role of G-protein coupled estrogen receptor 1 in mediating estrogenic protection against spinal cord injury.

Main Results: We show that G-protein coupled estrogen receptor 1 is mainly distributed in the ventral horn and white matter of the spinal cord, which is totally different from nuclear estrogen receptors. We also show that G-protein coupled estrogen receptor 1 is specifically expressed by neurons, oligodendrocytes, and microglial cells, but not astrocytes. Furthermore, estrogen treatment prevents spinal cord injury-induced apoptotic cell death and enhances functional recovery after spinal cord injury, which can be mimicked by the specific G-protein coupled estrogen receptor 1 agonist G-1 and inhibited by specific knockdown of G-protein coupled estrogen receptor 1 expression, but not pure nuclear ER antagonist ICI 182,780. Finally, we show that estrogen or G-1 up-regulates the protein expression level of G-protein coupled estrogen receptor 1 to intensify estrogenic effects during spinal cord injury.

Conclusions: These results reveal that G-protein coupled estrogen receptor 1 may mediate estrogenic neuroprotection against spinal cord injury, and underline the promising potential of estrogen with its new target G-protein coupled estrogen receptor 1 for the treatment of spinal cord injury patients.

© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

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