Treatment of traumatic brain injury with 17 alpha-ethinylestradiol-3-sulfate in a rat model

Abstract

OBJECTIVE 17 alpha-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 (similar to 10 minutes). In this study, EE-3-SO4 was 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 (PbtO(2)) 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-SO4 significantly lowered ICP while raising CPP and PbtO(2), compared with vehicle treatment in TBI-induced animals (p < 0.05). The mean size of cerebral edema of TBI animals treated with EE-3-SO4 was 25 3 mm(3) (mean SE), which was significantly smaller than that of vehicle-treated animals (67 +/- 6 mm(3), p < 0.001). Also, EE-3-SO4 treatment 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-SO4 for early TBI treatment.