Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury

Laboratory investigation

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Although there is evidence that estradiol has neuroprotective effects after traumatic brain injury (TBI) in female rats, it is unclear which estrogen receptor (ER) subtype, ERα or ERβ, mediates this effect. The authors therefore examined the roles of the different ERs in this effect. Here the authors used the ERα selective agonist propyl pyrazole triol (PPT) and the ERβ selective agonist diarylpropionitrile (DPN) alone and in combination in female rats to investigate this question.


Before the ovariectomized animals were injured using the Marmarou TBI technique, they were randomly divided into the following 9 groups: control, sham, TBI, vehicle, E1 (physiological dose of 17-β estradiol), E2 (pharmacological dose of 17-β estradiol), PPT, DPN, and PPT+DPN. Levels of blood-brain barrier (BBB) disruption (5 hours) and water content (24 hours) were evaluated after TBI. In groups receiving drugs or vehicle, treatment was administered as a single dose intraperitoneally 30 minutes after induction of TBI.


Results showed that brain edema or brain water content after TBI was lower (p < 0.001) in the E2, PPT, DPN, and PPT+DPN groups than it was in the vehicle group. After trauma, the Evans blue dye content or BBB permeability was significantly higher in the TBI and vehicle groups (p < 0.001) than in the E2, PPT, DPN, and PPT+DPN groups. The inhibitory effects of PPT+DPN on brain water content, neurological scores, and Evans blue dye content were the highest for all groups. Although both PPT and DPN increased neurological scores after TBI, PPT appears to be more effective in increasing neurological scores.


Neuroprotective effects of estradiol on brain edema, BBB permeability, and neurological scores are mediated through both ERα and ERβ. This may suggest a therapeutic potential in the brain trauma for ER-specific agonists.

Abbreviations used in this paper:BBB = blood-brain barrier; DMSO = dimethyl sulfoxide; DPN = diarylpropionitrile; E1 = physiological dose of 17-β estradiol; E2 = pharmacological dose of 17-β estradiol; ER = estrogen receptor; IL = interleukin; MMP-9 = matrix metalloproteinase–9; PPT = propyl pyrazole triol; TBI = traumatic brain injury; TNF = tumor necrosis factor; VCS = veterinary coma scale.

Article Information

Address correspondence to: Mohammad Khaksari, Ph.D., Physiology Research Center, School of Medicine, Kerman University of Medical Sciences, 22 Bahman Boulevard, Kerman 7614715977, Iran. email:

Please include this information when citing this paper: published online May 31, 2013; DOI: 10.3171/2013.4.JNS121636.

© AANS, except where prohibited by US copyright law.



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    A and B: Effects of the acute administration of 2 doses of estrogen (A) and selective agonists of ERs (PPT and DPN) on brain water content (%) after TBI in ovariectomized rats (B). C: Changes in percentage of water content after TBI compared with vehicle. There were 7 rats per group. ***p < 0.001 compared with vehicle. †††p < 0.001 compared with sham. §§§p < 0.001 compared with PPT and DPN. ##p < 0.01 higher than E2. ###p < 0.001 higher than E2, PPT, and DPN. Values represent the mean ± SEM. C = control; Veh = vehicle.

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    A and B: Effects of the acute administration of 2 doses of estrogen (A) and selective agonists of ERs (PPT and DPN) on Evans blue dye content (μg/g tissue) (%) after TBI in ovariectomized rats (B). C: Changes in percentage of Evans blue content after TBI compared with vehicle. There were 7 rats per group. ***p < 0.001 compared with vehicle. †††p < 0.001 compared with sham. #p < 0.05 higher than E2. ##p < 0.01 higher than E2. ###p < 0.001 higher than E2, PPT, and DPN. Values represent the mean ± SEM.

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    A and B: Comparison of the effects of acute administration of 2 doses of estrogen (A) and selective agonists of ERs (PPT and DPN) on neurological consequences as measured by the VCS at different time points after TBI (B) in ovariectomized rats. Higher scores (consisting of motor function, eye function, and respiration) correlated with better neurological outcomes. C: Changes in percentage of VCS scores after TBI compared with vehicle. ***p < 0.001 at 1, 4, and 24 hours after TBI for E2, PPT, DPN, and PPT+DPN compared with vehicle and at 4 and 24 hours for E1 compared with vehicle. †††p < 0.001 for all time points after TBI for sham compared with all other groups. aHigher than all other groups (E1, E2, PPT, and DPN) at all times after TBI (p < 0.001). bLess than all other groups (E2, PPT, DPN, and PPT+DPN) at 1 hour after TBI and less than E2, PPT, and PPT+DPN at 4 and 24 hours after TBI (p < 0.001). cLess than PPT at 4 and 24 hours after TBI and less than E2 and PPT at 24 hours after TBI (p < 0.001). Values represent the mean ± SEM.

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    Effects of estrogen administration on brain level of 17β-estradiol after TBI in ovariectomized rats (7 rats/group). 17-β estradiol was measured at 24 hours after injury. ***p < 0.001 compared with vehicle or E1. Values represent the mean ± SEM.



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