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 (Mg²⁺) and a significant increase in the amount of serum ionized calcium (Ca²⁺) relative to Mg²⁺ (Ca²⁺/Mg²⁺). For three hours, serum Mg²⁺ 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 Ca²⁺ (about 10%), but a significant increase in the amount of Ca²⁺/Mg²⁺ (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 Mg²⁺ and brain injury, the effect of Mg²⁺ treatment on posttraumatic histological changes (apoptotic changes) was examined following the weight-drop induced brain injury. At 30 min postinjury, animals treated with MgSO₄ (750 µmol/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 Mg²⁺ and the increase in the amount of Ca²⁺/Mg²⁺ 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 MgSO₄ may be effective in improving histological findings following experimental traumatic brain injury in rats.