実験的脳損傷に対するdexamethasoneの脳保護作用—作用発現のtime courseについて

TIME COURSE OF THE CEREBROPROTECTIVE EFFECT OF DEXAMETHASONE IN THE EXPERIMENTAL HEAD INJURY

　抄録　外傷性脳損傷に対するsteroidの治療効果についてはいまだ議論も多く結論は得られていない。しかも従来dose-responseの研究が主でtime courseをみたものはない。脳損傷を定量化したマウス頭部外傷モデルを用いdexamethasone （以下，Dx）の効果発現のtime courseを検討した。生後4週雄マウス（dd系，平均17.89）1,388匹を無麻酔下に頭部を固定し，平均5349—cmの衝撃を加えた。Dxは4mg／kgを30分，4, 6, 12, 18, 24時間前に腹腔内投与した。更に効果のあった群に対してactinomycin-D0.5mg／kgをDx投与1時間前に尾静脈より投与しその影響をみた。他に2, 4, 6, 8mg／kgを30分−4時間前に投与しdose-responseとtime couseとの関連を調べた。Dxの効果は意識障害，痙攣発生および死亡率を観察し判定した。4mg／kg投与では4-12上時間前で効果を認め効果発現までに4時間のtime lagがあることがわかった。actinomycin-D前処置はこれらの効果を統計的有意に抑制した。6-8mg／kgの大量投与は30分−2時間前でも効果を有し用量依存性のtime lag短縮傾向を認めた。以上の結果よりDxの効果は何らかの蛋白質生成を介して働くものと考えられ，治療効果を得るためには可能な限り早期に従来より大量の投与が必要となることが示唆された。

Despite the widespread use of glucocorticoids in patients with severe head injury, the usefulness is still controversial. In the past, the effect was investigated only in terms of dose-response rela-tionship. We have, however, studied the time factor for the administration of dexamethasone to obtain maximal beneficial effect together with investigating the influence of actinomycin-D, an inhibitor of messenger RNA synthesis, before dexamethasone treatment.

Awake male mice of dd-strain were restrained and subjected to head injury using a bakelite weight of 30 g dropped from a height of 17.8cmabove the skull. This injury resulted in imme-diate loss of consciousness in 100%, convulsive seizure in abuot 70% and death in about 30% of animals. The severity of consciousness disturbance was evaluated by a pair of indices in time inter-val : (1) time required for the recovery of right-ing reflex (RR) and (2) for the recovery of spontaneous movement (SM). 4mg/kg of dexame-thasone phosphate was given intraperitoneally 0.5, 4, 6, 12, 18 or 24 hours before injury. Acti-nomycin-D of O. 5 mg/kg was injected intrave-nously 1h before each dexamethasone treatment in separate animals. In the other group of animals, dose was changed with varying time course of dexamethasone pretreatment, e.g., 2, 4, 6 or 8 mg/kg given O. 5, 2 or 4 h before injury.

It was found that dexamethasone of 4 mg/kg pretreatment 4-12 hours significantly improved the recovery from consciousness disturbance and death rate. Actinomycin-D given before dexamethasone treatment completely abolished the protective effect of dexamethasone. These results indicate that a time interval at least for 4 hours is requir-ed for the induction of effect of dexamethasone which is possibly mediated by de novo synthesis of protein. However, if much higher doses are used, the beneficial effect appears in shorter interval such as 0.5 to 2 hours.

It would thus be warranted that glucocorticoids should be given in megadose as soon as possible in patients with severe head injury, hopefully by crew members of ambulance.