Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats

While a number of laboratories have begun to examine gender differences in outcome following experimental stroke, little is known about the relative response of male and female brains to traumatic injury. In the following series of experiments, we used the Marmarou impact-acceleration head injury model (with a 500-g, 1.5-m weight drop) to compare the pathophysiological responses of male and female rats to closed-head injury. Cortical blood flow (CBF; laser-doppler flowmetry), mean arterial blood pressure (MAP), blood gas levels, blood pH, and body temperature were measured preinjury and at regular intervals postinjury. Acute survival was assessed 1 h after injury. The role of estrogen in the observed gender differences was assessed by examining these physiological measures after injury in ovariectomized females, with or without 17β-estradiol replacement, and in intact males, with or without exogenous 17β-estradiol administration. In the first experiment, significantly more females (100%) survived the acute injury period (60 min) after injury than did males (72%). Survival appeared related to the magnitude and persistence of the posttraumatic drop in MAP. In a second experiment, females showed a less dramatic reduction in and better recovery of CBF than males. The gender difference in CBF was paralleled to some degree by differences in the pattern of MAP changes after injury. Differences in body weight, blood gas levels, or blood pH did not account for the gender difference in CBF. Postinjury CBF was higher in female and male rats given 2 weeks of daily 17β-estradiol injections prior to injury compared to those given the vehicle only. However, 17β-estradiol administration did not alter MAP, suggesting that the gender difference in CBF was not strictly due to MAP changes. Our findings suggest that estrogen plays a role in maintaining adequate cerebral perfusion in the acute period following closed-head injury. This protective mechanism may underlie the gender difference in acute survival observed in this study, and may help explain observations of better outcome in females than in males after brain injury. We conclude that CBF preservation is one mechanism by which estrogen is neuroprotective following traumatic brain injury. We hypothesize, based upon known effects of estrogen, that the beneficial microvascular effects of estrogen most likely involve a combination of endothelial nitric oxide synthase induction and an antioxidant effect.