The biochemical factors related to moderation of secondary or delayed damage to the central nervous system (CNS) remain undefined. We have recently demonstrated that the weight- drop induced moderate diffuse axonal injury (mDAI) in rats causes a rapid decline in serum ionized magnesium (Mg(2+)) and a significant increase in the amount of serum ionized calcium (Ca(2+)) relative to Mg(2+) (Ca(2+)/ Mg(2+)). For three hours, serum Mg(2+) levels remained significantly depressed at 76% of preinjury values (p < 0.05), but total serum magnesium remained unchanged (tMg, p > 0.05). Head trauma resulted in a small decrease of Ca(2+) (about 10%), but a significant increase in the amount of Ca(2+)/Mg(2+) (mean value in control group: in injured group for 3 hours after trauma =4.65 +/- 0.012 : 5.69 +/- 0.015, p < 0.05) was observed. In order to further investigate the relationship between Mg(2+) and brain injury, the effect of Mg(2+) treatment on posttraumatic histological changes (apoptotic changes) was examined following the weight-drop induced brain injury. At 30 min postinjury, animals treated with MgSO(4) (750 micromol/kg) showed significant improvements of apoptotic changes when compared to the control group (54.8 +/- 1.7, 51.5 +/- 3.2 at 12, 24 h in control group, 24.8 +/- 2.6, 20.5 +/- 1.4 at 12, 24 h in treated group, p < 0.05). The early decline in serum Mg(2+) and the increase in the amount of Ca(2+)/Mg(2+) immediately following brain trauma uncovered by these findings suggest that they may be a critical factor in the development of irreversible tissue injury. If this proves to be the case, treatment with MgSO(4) may be effective in improving histological findings following experimental traumatic brain injury in rats.