Treatment of traumatic brain injury with 17α-ethinylestradiol-3-sulfate in a rat model.
OBJECTIVE 17α-ethynylestradiol-3-sulfate (EE-3-SO4) is a highly water-soluble synthetic estrogen that has an extended half-life (∼ 10 hours) over that of naturally occurring estrogen (∼ 10 minutes). In this study, EE-3-SO4was evaluated in a lateral fluid percussion-induced traumatic brain injury (TBI) model in rats. METHODS A total of 9 groups of Sprague-Dawley rats underwent craniectomy. Twenty-four hours later, lateral fluid percussion was applied to 6 groups of animals to induce TBI; the remaining 3 groups served as sham control groups. EE-3-SO4(1 mg/kg body weight in 0.4 ml/kg body weight) or saline (vehicle control) was injected intravenously 1 hour after TBI; saline was injected in all sham animals. One day after EE-3-SO4/saline injection, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and partial brain oxygen pressure (PbtO2) were measured in Groups 1-3 (2 TBI groups and 1 sham group), and brain edema, diffusion axonal injury, and cerebral glycolysis were assessed in Groups 4-6 using MRI T2 mapping, diffusion tensor imaging (DTI), and FDG-PET imaging, respectively. Four days after dosing, the open-field anxiety of animals was assessed in Groups 7-9 by measuring the duration that each animal spent in the center area of an open chamber during 4 minutes of monitoring. RESULTS EE-3-SO4significantly lowered ICP while raising CPP and PbtO2, compared with vehicle treatment in TBI-induced animals (p < 0.05). The mean size of cerebral edema of TBI animals treated with EE-3-SO4was 25 ± 3 mm3(mean ± SE), which was significantly smaller than that of vehicle-treated animals (67 ± 6 mm3, p < 0.001). Also, EE-3-SO4treatment significantly increased the fractional anisotropy of the white matter in the ipsilateral side (p = 0.003) and cerebral glycolysis (p = 0.014). The mean duration that EE-3-SO4-treated animals spent in the center area was 12 ± 2 seconds, which was significantly longer than that of vehicle-treated animals (4 ± 1 seconds; p = 0.008) but not different from that of sham animals (11 ± 3 seconds; p > 0.05). CONCLUSIONS These data support the clinical use of EE-3-SO4for early TBI treatment.
Departments of 1 Radiology.
Harrison
H
Kim
Surgery, and.
Tao
T
Yu
Department of Physiology, Uludag University, Bursa, Turkey.
Betul
B
Cam-Etoz
Developmental and Integrative Biology, University of Alabama at Birmingham, Alabama; and.
Thomas
T
van Groen
Surgery, and.
William J
WJ
Hubbard
Surgery, and.
Irshad H
IH
Chaudry
D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy*; D004195:Disease Models, Animal; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D004997:Ethinyl Estradiol; C059147:ethinyl estradiol-17-sulfate
CPP = cerebral perfusion pressure; DAI = diffuse axonal injury; DTI = diffusion tensor imaging; E2 = 17β-estradiol; E2-SO4 = 17β-estradiol sulfate; EE-3-SO4 = 17α-ethynylestradiol-3-sulfate; EE= 17α-ethinyl estradiol; ICP = intracranial pressure; PbtO2 = partial brain oxygen pressure; SUV = standardized uptake value; T2 mapping; TBI; TBI = traumatic brain injury; behavioral test; diffusion tensor imaging; intracranial pressure; positron emission tomography; traumatic brain injury