17β-Estradiol Confers Protection after Traumatic Brain Injury in the Rat and Involves Activation of G Protein-Coupled Estrogen Receptor 1

Abstract

Traumatic brain injury (TBI) is a significant public health problem in the United States. Despite preclinical success of various drugs, to date all clinical trials investigating potential therapeutics have failed. Recently, sex steroid hormones have sparked interest as possible neuroprotective agents after traumatic injury. One of these is 17b-estradiol (E2), the most abundant and potent endogenous vertebrate estrogen. The goal of our study was to investigate the acute potential protective effects of E2 or the specific G protein-coupled estrogen receptor 1 (GPER) agonist G-1 when administered in an intravenous bolus dose 1 hour post-injury in the lateral fluid percussion (LFP) rodent model of TBI. The results of this study show that, when assessed at 24 hours post-injury, E2 or G-1 confers protection in adult male rats subjected to LFP brain injury. Specifically, we found that an acute bolus dose of E2 or G-1 administered intravenously 1 hour post-TBI significantly increases neuronal survival in the ipsilateral CA 2/3 region of the hippocampus and decreases neuronal degeneration and apoptotic cell death in both the ipsilateral cortex and CA 2/3 region of the hippocampus. We also report a significant reduction in astrogliosis in the ipsilateral cortex, hilus, and CA 2/3 region of the hippocampus. Finally, these effects were observed to be chiefly dose-dependent for E2, with the 5 mg/kg dose generating a more robust level of protection. Our findings further elucidate estrogenic compounds as a clinically relevant pharmacotherapeutic strategy for treatment of secondary injury following TBI, and intriguingly, reveal a novel potential therapeutic target in GPER.

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

“…It seems that in many models of diseases the activation of the master transcription factor, NF-jB, which controls inflammatory and immune pathways, is implicated. A very similar effect on rat spinal cord injury was observed with estrogen and is supposedly orchestrated via glucocorticoid receptor (67,110,129,185,243). A significant association between testosterone level and severity of SCI has been reported (79,83).…”

Traumatic Brain Injury Induces Alterations in Cortical Glutamate Uptake without a Reduction in Glutamate Transporter-1 Protein Expression

“…22,23 Briefly, animals were anesthetized with 4% isoflurane gas in an O 2 carrier for 4 minutes, followed by intraperitoneal injection of 100/10 mg/kg mixture of ketamine/xylazine; anesthesia was maintained via ventilation with 1.5-3% isoflurane gas for the duration of surgery. Normothermia was maintained throughout surgery by keeping the animals on a water-jacketed heating pad.…”

Bulk derivatization and cation exchange restricted access media-based trap-and-elute liquid chromatography–mass spectrometry method for determination of trace estrogens in serum

“…Decreasing incidence of stroke-related mortality was described in postmenopausal women using hormonal therapy [9,10]. It was already elucidated as a possible therapeutic treatment for traumatic brain injury [11,12]. For a better understanding of the biological functions and connections to diseases, the ability to sensitively detect estrogens in biological fluids is essential.…”