Abstract
The importance of small variations in brain temperature on ischremie and traumatic outcome has been reported in a large number of experimental models. Although therapeutic hypothermia has been demonstrated in some patient populations, negative findings have been reported in others. The limitations of the effectiveness of hypothermia may be related to several factors, including therapeutic window, optimal levels and durations of cooling, rewarming protocol, injury severity, and gender. The purpose of this study was to assess the importance of several of these factors on hypothermie protection in an established model of fluid-percussion (F-P) brain injury. Male and female Sprague-Dawley rats underwent moderate F-P brain injury with or without periods of secondary hypoxia. Selective brain hypothermia (33°–34°C) was initiated 30 min after traumatic brain injury (TBI) and maintained for a 4-h period. Following the hypothermie treatment, animals were rapidly (30 min) or slowly (90 min) rewarmed. Three days following TBI, animals were perfusion-fixed and quantitatively assessed for contusion volume, numbers of NeuN-positive cortical neurons, and axonal pathology. Post-traumatic hypothermia significantly reduced contusion volume and protected against selective neuronal damage in male, but not female, rats. Interestingly, female rats that had been previously ovariectomized demonstrated protection with hypothermia. Hypothermie protection was not observed in TBI animals that underwent a secondary hypoxic insult when rapid rewarming was conducted. However, with slow rewarming, therapeutic hypothermia decreased overall contusion volume in TBI rats with secondary hypoxia. To continue investigating the importance of gender on traumatic outcome, the effects of post-traumatic hyperthermia in female rats was studied. Evidence was obtained for female rats being protected against a hyperthermic insult. Taken together, these experiments emphasize several factors, including gender, that may be important in determining the efficacy of therapeutic hypothermia in experimental models of TBI. Similar factors may be important in clinical neuroprotection studies utilizing hypothermia protocols.