Brain Research, 608 (1993) 95-100 95 © 1993 Elsevier Science Publishers B.V. All rights reserved 0006-8993/93/$06.00 BRES 18687 Estrogen improves biochemical and neurologic outcome following traumatic brain injury in male rats, but not in females Claire S. Emerson, John P. Headrick and Robert Vink Department of Chemistry and Biochemistry, James Cook University of North Queensland, Townsville, Qld (Australia) (Accepted 27 October 1992) Key words: Magnesium; Nuclear magnetic resonance; Trauma Phosphorus magnetic resonance spectroscopy was used in conjunction with neurologic motor function tests to assess the effects of estrogen on biochemical and neurologic outcome following traumatic brain injury in male and female rats. Male (n = 18) and female (n = 18) rats were randomly assigned into three groups, and 4 h prior to injury received either 17/3-estradiol (144/zg/kg intraperitoneally), equal volume vehicle (30% ethanol in saline), or no treatment. Traumatic brain injury was induced at 2.8 atm using a fluid percussion injury device, and animals monitored for 4 h using phosphorus magnetic resonance spectroscopy to determine brain intracellular pH, free magnesium concentration and cytosolic phosphorylation potential. Males treated with estrogen demonstrated a significant improvement in free magnesium concentration, and slightly improved values of cytosolic phosphorylation potential after trauma when compared to controls. There was also a significant improvement in post-traumatic motor function at 1 week after trauma. In contrast, estrogen treatment in females lowered cytosolic phosphorylation potential after trauma, but did not affect free magnesium concentration after trauma. Mortality in all female groups was significantly worse than in males. We conclude that estrogen is protective in males, but exacerbates brain injury in females through effects mediated by estrogen receptor binding. INTRODUCTION Secondary events are regarded as playing a critical role in the development of irreversible tissue damage after trauma to the central nervous system. These secondary events occur hours-to-days after the primary insult, and are made up of a variety of biochemical and physiological events leading ultimately to neuronal cell death 12. The fact that these secondary events are de- layed provides an opportunity for therapeutic interven- tion designed to prevent or attenuate the injury pro- cess. However, the development of appropriate phar- macotherapies that may be used for the treatment of neurotrauma first requires the characterization of the secondary events and their interelationship with one another. Most studies to date have utilized male ani- mals, and various treatments have been developed on the basis of these results. Recent studies, however, suggest that endogenous female hormones may affect a number of processes involved in the development of secondary injury. The steroid hormone estrogen, in particular, has been the subject of a number of studies, and conflicting reports suggest that it is both protec- tive l° and deleterious 22 with respect to neuronal cell death. Those studies demonstrating a protective action of estrogen suggest that this protection is a result of the hormone's lipid antioxidant properties ~° while studies reporting its potential deleterious actions show that estrogen potentiates neuronal responses to excita- tory amino acids 22. We have previously demonstrated that phosphorus magnetic resonance spectroscopy (MRS) can be used to monitor a number of metabolic secondary injury factors following a traumatic event 2s. Moreover, these studies have demonstrated that the acute changes in intracellular free magnesium concentration and cytoso- lic phosphorylation potential following traumatic brain injury are correlated to neurologic outcome 24'27'28. Es- trogen has been demonstrated to affect both free mag- nesium concentration and energy metabolism in tis- sues 3. Accordingly, we have used phosphorus MRS to monitor the effects of estrogen on brain free magne- sium concentration and energy metabolism in trauma- tized male and female rats. In addition to MRS, we Correspondence: R. Vink, Department of Chemistry and Biochemistry, James Cook University, Townsville, Qld 4811, Australia. Fax: (61) (77) 25 1394.