エンドトキシン（ET）持続注入によるラット脳障害—Methylprednisoloneの脳保護効果

Brain Injury Induced by Continuous Infusion of Endotoxin in Rats : Protective Effects of Methylprednisolone on Intracerebral Blood Vessels

　ドンリュー系雄性ラット122匹に対しmethylprednisolone（MP）無投与をエンドトキシン（ET）血症基礎群（I群）とし，MP 0.2mg，1.0mg，2.0mg，20.0mg／kgを前投与（II群），ET投与開始48時間後MP 20.0mg／kg 1回と48，72時間後の2回投与（III群），3日間計3回（各群それぞれ2.0mg，20.0mg，および100.0mg／kg）のMP投与（IV群）を行った。I群には83％に多発性脳内出血性病変がみられたが，MP2.0mg／kg,20.0mg／kg前投与（II群）およびIV群では出血性病巣発生頻度に有意の減少がみられた。脳内血管の電顕的検索ではI群に大脳皮質血管周囲のdiapedesisと血管内皮細胞の突出やvacuoleを認めたのに対してMP 20.0mg／kg前投与（II群）では血管に変化が認められなかった。III群では脳内出血性病変発生に対する防御効果はみられず，ET血症発生前のMP予防的投与がDIC脳内出血性病変発生に際し保護効果があると考えられた。

Hemorrhagic intracerebral lesions, analogous tomultiple punctate hemorrhagic necrosis seen in the brain of human disseminated intravascular coagula-tion (DIC), can be induced in rats by continuous intravenous infusion of E. coli endotoxin lipopoly-saccharide (ET) at 88.5 μg/hour. The occurrence of cerebral lesions increases with time of ET infusion initially, but levels off after 120 hours of the continu-ous administration. To investigate protective effects of methylprednisolone (MP) against intracerebral vascular injury, 122 male rats were divided into the basic endotoxemic rats without MP medication (Group 1), and MP medication of 0.2mg/kg body weight, 1.0mg/kg, 2.0mg/kg and 20.0mg/kg immedi-ately before induction of endotoxemia (Groups 2-5), one dose of 20.0mg/kg MP at 48 hours and 2 doses at 48 and 72 hours after induction of endotox-emia (Groups 6-7), and 3 doses each of 2.0mg/kg, 20.0mg/kg and 100.0mg/kg MP for 3 days immedi-ately before and at 24 and 48 hours after induction of endotoxemia (Groups 8-10). All surviving rats were autopsied after 120 hours of ET infusion and histologic sections were made. Multiple hemorr-hagic intracerebral lesions developed in 83% (10/ 12) of Group 1 rats, whereas the frequency of brain lesions in Groups 4, 5, 8, 9 and 10 was significantly lower than that in Group 1 (p＜0.05). Electron microscopically, the frontal lobe cortex of Group 1 after 120 hours of ET infusion showed suben-dothelial dilatation containing macrophages, and perivascular accumulation of erythrocytes (diape-desis). In contrast, the frontal lobe cortex of Group 5 revealed no appreciable electron microscopic changes of intracerebral blood vessels. This experi-ment showed that the rats receiving 2.0 mg/kg or larger doses of MP prior to induction of endotox-emia developed brain lesions significantly less fre-quently than Group 1. Electron microscopy on intracerebral blood vessels of the MP-administered rats (Group 5) as compared with Group 1 supported protective effects of MP against vascular injury. The doses of 20 to 100 mg MP per kg body weight for 3 days administered to the rats of Groups 9 and 10 corresponded to the doses of therapeutic "pulse" administration in human cases. However, the results of our study showed that only the administration of MP prior to, not after, induction of endotoxemia proved to be effective for protection of the brain. This prophylactic MP administration proved also effective on protection against vascular injuries in other viscera of endotoxemic rats.