title: Estrone is neuroprotective in rats after traumatic brain injury.
abstract: In various animal and human studies, early administration of 17β-estradiol, a strong antioxidant, anti-inflammatory, and anti-apoptotic agent, significantly decreases the severity of injury in the brain associated with cell death. Estrone, the predominant estrogen in postmenopausal women, has been shown to be a promising neuroprotective agent. The overall goal of this project was to determine if estrone mitigates secondary injury following traumatic brain injury (TBI) in rats. Male rats were given either placebo (corn oil) or estrone (0.5 mg/kg) at 30 min after severe TBI. Using a controlled cortical impact device in rats that underwent a craniotomy, the right parietal cortex was injured using the impactor tip. Non-injured control and sham animals were also included. At 72 h following injury, the animals were perfused intracardially with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for TUNEL-positive cells. Estrone decreased cortical lesion volume (p<0.01) and neuronal injury (p<0.001), and it reduced cerebral cortical levels of TUNEL-positive staining (p<0.0001), and decreased numbers of TUNEL-positive cells in the corpus callosum (p<0.03). We assessed the levels of β-amyloid in the injured animals and found that estrone significantly decreased the cortical levels of β-amyloid after brain injury. Cortical levels of phospho-ERK1/2 were significantly (p<0.01) increased by estrone. This increase was associated with an increase in phospho-CREB levels (p<0.021), and brain-derived neurotrophic factor (BDNF) expression (p<0.0006). In conclusion, estrone given acutely after injury increases the signaling of protective pathways such as the ERK1/2 and BDNF pathways, decreases ischemic secondary injury, and decreases apoptotic-mediated cell death. These results suggest that estrone may afford protection to those suffering from TBI.
authors.affiliation: D/FW Center for Resuscitation Research, Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9160, USA. joshua.gatson@utsw.edu
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Gatson
authors.forename: Ming-Mei
authors.initials: MM
authors.lastname: Liu
authors.forename: Kareem
authors.initials: K
authors.lastname: Abdelfattah
authors.forename: Jane G
authors.initials: JG
authors.lastname: Wigginton
authors.forename: Scott
authors.initials: S
authors.lastname: Smith
authors.forename: Steven
authors.initials: S
authors.lastname: Wolf
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Minei
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002540:Cerebral Cortex / Q000293:injuries / Q000473:pathology; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004970:Estrone / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009414:Nerve Growth Factors / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents; D016612:Paraffin Embedding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013238:Stereotaxic Techniques
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D004970:Estrone