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

Abstract

OBJECTIVE17α-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-SO4 was evaluated in a lateral fluid percussion–induced traumatic brain injury (TBI) model in rats.METHODSA 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.RESULTSEE-3-SO4 significantly 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-SO4 was 25 ± 3 mm3 (mean ± SE), which was significantly smaller than that of vehicle-treated animals (67 ± 6 mm3, 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).CONCLUSIONSThese data support the clinical use of EE-3-SO4 for early TBI treatment.

Postinjury weight rather than cognitive or behavioral impairment predicts development of posttraumatic epilepsy after lateral fluid‐percussion injury in rats

“…Similarly, we found no major effect of lateral FPI on performance in the open-field test. Previously, Kim et al 39 and Fucich et al 40 assessed rats with lateral FPI at D4 and D7 postinjury, respectively, and found that the injured rats spent less time than controls exploring the center of the open field. Similarly, Schultz et al 14 reported that rats with severe lateral FPI spent slightly less time than sham-operated controls in the inner arena at 1 and 3 months, but not at 6 months post-TBI; however, there was no difference between the epileptic and nonepileptic animals.…”

Gender differences in trauma, shock and sepsis

“…Studies have also shown that administration of estrogen 1 hour following traumatic brain injury produces various beneficial effects, such as markedly reduced cerebral edema, decreased neuronal degeneration and improvement of memory and cognitive functions [ 57 – 59 ]. Furthermore, studies have shown that estrogen administration following spinal cord injury also produces salutary effects [ 60 , 61 ].…”

Diffusion Tensor Imaging-Based Studies at the Group-Level Applied to Animal Models of Neurodegenerative Diseases

“…Finally, DTI-MRI has been used as read-out of treatment efficacy in rodents' models of TBI. In particular, DTI has revealed the beneficial effect on white matter integrity of activation of mitochondrial calcium fluxes (Parent et al, 2020 ), of autophagy modulators (Medina et al, 2017 ; Yin et al, 2018 ), estrogens (Kim et al, 2015 , 2017 ), metamphetamine (Ding et al, 2013 ), erythropoietin (Robinson et al, 2016 , 2018 ), tissue plasminogen activator (in mice; Xia et al, 2018 ), mGluR5 (in mice; Byrnes et al, 2012 ), and dietary modulations (Shultz et al, 2015 ; Schober et al, 2016 ; Tan et al, 2016 ). Notably, the detrimental effect of alcohol in TBI was also investigated by DTI (Kong et al, 2013 ).…”