We hypothesized that post-ischemic hypothermia plays an important role in magnesium mediated neuroprotection following global cerebral ischemia. To test this hypothesis, we subjected rats to 8 min of global cerebral ischemia and magnesium treatment with and without post-ischemic body temperature maintenance. In Group 1, rats received an intravenously administered loading dose (LD) of 360 micromol/kg MgSO4 immediately before ischemia followed by a 48-h intravenous infusion (IVI) at either 60, 120 or 240 micromol/kg/h. Animal body temperature was kept at 37+/-0.2 degrees C during ischemia and between 36.6 and 37.8 degrees C for 6 h after ischemia. In Group 2, rats received a 360 micromol/kg MgSO4 LD followed by a 48-h IVI of either 120 or 240 micromol/kg/h MgSO4. In this group, body temperature following ischemia was monitored but not regulated. Control animals in Groups 1 and 2 received normal saline. Seven days after ischemia, hippocampal CA1 neurons were histologically examined. All Group 1 MgSO4-treated and control animals demonstrated less than 6% hippocampal CA1 neuronal survival. In Group 2, the rectal temperature of MgSO4-treated and control animals spontaneously dropped as low as 35.4 degrees C during the 6-h post-ischemia monitoring period. In addition, Group 2 animals that received the LD followed by an IVI of 120 or 240 micromol/kg/h MgSO4 demonstrated 34% (p<0.05) and 20% (p=0.936) CA1 neuronal survival, respectively. The CA1 neuronal survival in saline-treated control animals in both groups was less than 6%. Our data demonstrate only the combination of MgSO4 treatment and post-ischemic mild hypothermia is neuroprotective following global ischemia.