Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic injury by activating specific mechanisms. In this study, we tested the hypothesis that IPC attenuates postischemic neuronal death via
heme oxygenase-1 (HO-1). Animals used in this study were randomly assigned to 4 groups;
sham-operated group,
ischemia-operated group, IPC plus (+)
sham-operated group and IPC+ischemia-operated group. IPC was induced by subjecting gerbils to 2min of
ischemia followed by 1 day of recovery. A significant loss of neurons was observed in pyramidal neurons of the hippocampal CA1 region (CA1) in the
ischemia-operated groups at 5 days postischemia. In the IPC+ischemia-operated groups, CA1 pyramidal neurons were well protected. The level of HO-1
protein and its activity increased significantly in the CA1 of the IPC+sham-operated group, and the level and activity was maintained in all the time after
ischemia-reperfusion compared with the
ischemia-operated groups. HO-1 immunoreactivity was induced in the CA1 pyramidal neurons in both IPC+sham-operated- and IPC+ischemia-operated groups. We also found that levels or immunoreactivities of
superoxide anion,
8-hydroxy-2'-deoxyguanosine and
4-hydroxy-2-nonenal were significantly decreased in the CA1 of both IPC+sham-operated- and IPC+ischemia-operated groups. Whereas, treatment with
zinc protoporphyrin IX (a HO-1 inhibitor) into the IPC+ischemia-operated groups did not preserve the IPC-mediated increase of HO-1 and lost beneficial effects of IPC by inhibiting
ischemia-induced DNA damage and lipid peroxidation. In brief, IPC protects CA1 pyramidal neurons from ischemic injury by upregulating HO-1, and we suggest that the enhancement of HO-1 expression by IPC may be a legitimate strategy for a therapeutic intervention of cerebral ischemic damage.