Gender and Estrogen Manipulation Do Not Affect Traumatic Brain Injury in Mice

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Abstract
As epidemiological data have suggested that female patients may have improved clinical prognoses following traumatic brain injury (TBI) compared to males, we designed experiments to determine the role of gender and estrogen in TBI-induced brain injury and inflammation in rodents. To this end, male and female C57Bl/6 mice were separated into the following four groups: intact males, intact females with vehicle supplementation, ovariectomized females with vehicle supplementation, and ovariectomized females with estrogen supplementation. All mice were subjected to a controlled cortical impact model of TBI, and cortical injury, hippocampal degeneration, microglial activation, and brain cytokine expression were analyzed after injury. Additionally, the spleens were harvested and cytokine release from cultured splenic cells was measured in response to specific stimuli. Data indicate that TBI-induced cortical and hippocampal injury, as well as injury-related microglial activation were not significantly affected by gender or estrogen manipulation. Conversely, brain levels of MCP-1 and IL-6 were significantly increased in males and intact females following TBI, but not in female mice that had been ovariectomized and supplemented with either estrogen or vehicle. Evaluation of splenic responses showed that the spleen was only moderately affected by TBI, and furthermore that spleens isolated from mice that had been given estrogen supplementation showed significantly higher release of the anti-inflammatory cytokine IL-4, regardless of the presence of absence of TBI. Overall, these data indicate that while estrogen can modulate immune responses, and indeed can predispose splenic responses towards and anti-inflammatory phenotype, these effects do not translate to decreased brain injury or inflammation following TBI in mice.