Increase in endogenous brain superoxide dismutase as a potential mechanismof lipopolysaccharide-induced brain ischemic tolerance

A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours b efore 60-minute middle cerebral artery occlusion, induced a delayed neuropr otection proven by the significant decrease (-35%) of brain infarct volume in comparison with control, whereas infarct Volumes remained unchanged in r ats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotect ive effect of LPS was induced only with low doses (0.25 to 1 mg/kg), wherea s this effect disappeared with a higher dose (2 mg/kg). The delayed neuropr otection of LPS was induced in the cortical part of the infarcted zone, not in the subcortical part. The beneficial effect of LPS on consequences of m iddle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) a nd indomethacin (3 mg/kp) administered 1 hour before LPS, whereas both drug s had no direct effect on infarct Volume by themselves, suggesting that act ivation of inflammatory pathway is involved in the development of LPS-induc ed brain ischemic tolerance. Preadministration of cycloheximide, an inhibit or of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechan ism. Superoxide dismutase (SOD) could be one of the synthesized proteins be cause Lipopolysaccharide increased SOD brain activity 72 hours, but not 12 hours, after its administration, which paralleled the development of brain ischemic tolerance. In contrast, catalase brain activity remained unchanged after LPS administration. The LPS-induced delayed increase in SOD brain co ntent was suppressed by a previous administration of indomethacin. These da ta suggest that the delayed neuroprotective effect of low doses of LPS is m ediated by an increased synthesis of brain SOD that could be triggered by a ctivation of inflammatory pathway.