Durmaz Ramazan, Ertilav Kemal, Akyüz Fahrettin, Kanbak Güngör, Bildirici Kismet, Tel Eşref
Department of Neurosurgery, Medical Faculty of Osmangazi University, 26480 Eskişehir, Turkey.
J Neurol Sci. 2003 Nov 15;215(1-2):87-93. doi: 10.1016/s0022-510x(03)00207-7.
The aim of the present study was to determine the potential therapeutic value of 21-aminosteroid U-74389G, on blood-brain barrier (BBB) breakdown and edema in association with the changes in synaptosomal Na(+)/K(+) and Mg(2+)/Ca(2+)-ATPase activities in rat brain subjected to post-ischemic reperfusion injury. Brain ischemia was achieved by means of four-vessel occlusion model for 25 min and animals were sacrificed after 12 h reperfusion. An increase of cerebral tissue water content, blood-brain disruption and the changes of synaptosomal Na(+)/K(+) and Mg(2+)/Ca(2+)-ATPases activities were evaluated. U-74389G was given intraperitoneally at two times as 5 mg/kg at 10 min prior to ischemia and at the beginning of reperfusion. Edema was determined by means of wet-dried weight method, and BBB of extravasation of Evan's blue dye. Extravasation of Evan's blue dye into brain following ischemia and reperfusion was 2.4-fold of control value and brought close to control levels by the effect of U-74389G (p<0.001). Post-ischemic reperfusion injury caused an increase of 3.7% in tissue water content of whole brain and administration of U-74389G lowered the cerebral edema (p<0.001). The loses in the Na(+)/K(+)-ATPase and Mg(2+)/Ca(2+)-ATPase activities occurred as 42.1% (p<0.01) and 65.7% (p<0.001) of control value, respectively. While Mg(2+)/Ca(2+)-ATPase activity was enhanced compared to vehicle-treated group of animals (p<0.01), Na(+)/K(+)-ATPase activity was fully recovered when compared to control by U-74389G (p>0.05). U-74389G also significantly attenuated neuronal necrosis (p<0.001) which was determined in the hippocampal CA1 subfield. Blood-brain barrier protection, attenuation of brain edema and neuronal necrosis concomitant with the stabilizing of membrane-bound enzymes brought about by the effect of U-74389G suggest that 21-aminosteroids are worthy of consideration in the acute treatment of cerebral ischemia.
本研究的目的是确定21-氨基类固醇U-74389G对缺血后再灌注损伤大鼠脑血脑屏障（BBB）破坏和水肿的潜在治疗价值，以及与突触体Na(+)/K(+)和Mg(2+)/Ca(2+)-ATP酶活性变化的关系。通过四血管闭塞模型造成脑缺血25分钟，再灌注12小时后处死动物。评估脑组织含水量的增加、血脑屏障破坏以及突触体Na(+)/K(+)和Mg(2+)/Ca(2+)-ATP酶活性的变化。在缺血前10分钟和再灌注开始时，以5mg/kg的剂量分两次腹腔注射U-74389G。采用干湿重法测定水肿，通过伊文思蓝染料外渗评估血脑屏障。缺血再灌注后伊文思蓝染料向脑内的外渗是对照值的2.4倍，而U-74389G的作用使其接近对照水平（p<0.001）。缺血后再灌注损伤使全脑组织含水量增加3.7%，而U-74389G的给药降低了脑水肿（p<0.001）。Na(+)/K(+)-ATP酶和Mg(2+)/Ca(2+)-ATP酶活性分别下降至对照值的42.1%（p<0.01）和65.7%（p<0.001）。与给予赋形剂的动物组相比，U-74389G使Mg(2+)/Ca(2+)-ATP酶活性增强（p<0.01），与对照相比，U-74389G使Na(+)/K(+)-ATP酶活性完全恢复（p>0.05）。U-74389G还显著减轻了海马CA1亚区的神经元坏死（p<0.001）。U-74389G的作用对血脑屏障的保护、脑水肿的减轻和神经元坏死的减轻以及膜结合酶的稳定表明，21-氨基类固醇在脑缺血的急性治疗中值得考虑。
