Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance
Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance
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DOI：
10.1097/00004647-200008000-00004
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发表时间：
2000-08-01
影响因子：
6.3
通讯作者：
Dupuis, B
中科院分区：
文献类型：
--
作者：
Bordet, R;Deplanque, D;Dupuis, B
在大脑中动脉闭塞60分钟前72小时给予低剂量（0.5 mg/kg）脂多糖（LPS）诱导延迟的神经保护，其通过与对照相比脑梗死体积的显著减少（~ 35%）来证明，而在缺血前12、24或168小时处理的大鼠中梗死体积保持不变。LPS的这种延迟的神经保护作用仅在低剂量（0.25至1 mg/kg）下诱导，而这种作用在较高剂量（2 mg/kg）下消失。LPS的延迟性神经保护作用在梗死区的皮质部分，而不是在皮质下部分。LPS对大脑中动脉闭塞后果的有益作用被LPS前1小时给予的地塞米松（3 mg/kg）和吲哚美辛（3 mg/kp）抑制，而这两种药物本身对梗死体积没有直接影响，这表明炎症通路的激活参与LPS诱导的脑缺血耐受的发展。预先给予放线菌酮（一种蛋白质合成抑制剂）也阻断了LPS诱导的脑缺血耐受，这表明蛋白质合成也是必要的介导机制。超氧化物歧化酶（SOD）可能是合成的蛋白质之一，因为脂多糖在给药后72小时增加了SOD脑活性，而不是12小时，从而阻碍了脑缺血耐受的形成。相反，过氧化氢酶脑活性保持不变后LPS管理。LPS诱导的SOD脑含量的延迟增加被先前的吲哚美辛给药抑制。这些数据表明，低剂量LPS的延迟神经保护作用是通过增加脑SOD的合成介导的，这可能是由炎症通路的激活触发的。
A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours before 60-minute middle cerebral artery occlusion, induced a delayed neuroprotection proven by the significant decrease (-35%) of brain infarct volume in comparison with control, whereas infarct Volumes remained unchanged in rats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotective effect of LPS was induced only with low doses (0.25 to 1 mg/kg), whereas this effect disappeared with a higher dose (2 mg/kg). The delayed neuroprotection 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 middle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) and indomethacin (3 mg/kp) administered 1 hour before LPS, whereas both drugs had no direct effect on infarct Volume by themselves, suggesting that activation of inflammatory pathway is involved in the development of LPS-induced brain ischemic tolerance. Preadministration of cycloheximide, an inhibitor of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechanism. Superoxide dismutase (SOD) could be one of the synthesized proteins because 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 content was suppressed by a previous administration of indomethacin. These data suggest that the delayed neuroprotective effect of low doses of LPS is mediated by an increased synthesis of brain SOD that could be triggered by activation of inflammatory pathway.