Clemens J A, Saunders R D, Ho P P, Phebus L A, Panetta J A
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0814.
Stroke. 1993 May;24(5):716-22; discussion 722-3. doi: 10.1161/01.str.24.5.716.
In the rat four-vessel occlusion model with 30 minutes of ischemia most agents have failed to be of benefit when given after ischemia. Because postischemia administration is more clinically relevant, we evaluated the antioxidant LY231617 (2,6-bis(1,1-dimethylethyl)-4-[[(1-ethyl)amino]methyl]phenol hydrochloride]) when administered after 30 minutes of four-vessel occlusion.
Male Wistar rats were subjected to 30 minutes of four-vessel occlusion. LY231617 was either given orally 30 minutes before ischemia or intravenously beginning at 30 minutes after the onset of ischemia. Hippocampal CA1 layer and striatal damage were rated on a scale of 0-3 (0, no damage; 3, > 90% cell loss). We also evaluated the ability of LY231617 to prevent iron-dependent lipid peroxidation and to prevent hydrogen peroxide-induced neuronal death of hippocampal neurons in primary culture by exposing cultures to a 50-microM concentration of hydrogen peroxide for 15 minutes in the presence of LY231617.
Oral administration of LY231617 reduced both striatal and hippocampal CA1 damage by > 75% (p < 0.0001). In two separate experiments in which LY231617 was given intravenously beginning 30 minutes after occlusion, hippocampal and striatal damage were reduced by approximately 50% (p < 0.03) in the first experiment and by approximately 41% (p < 0.02) in the second experiment. Addition of 5 microM of LY231617 to primary hippocampal neuronal cultures antagonized the lethal effect of hydrogen peroxide (p < 0.05). Iron-dependent lipid peroxidation was also inhibited in a dose-related fashion.
The significant reduction of ischemia-induced or hydrogen peroxide-induced neuronal damage and inhibition of lipid peroxidation by LY231617 observed in this study suggest that reactive oxygen intermediates play an important role in the events leading to neuronal death after global ischemia/reperfusion.
在大鼠四动脉闭塞模型中，缺血30分钟后，多数药物在缺血后给药时未能显示出有益效果。由于缺血后给药在临床上更具相关性，我们评估了抗氧化剂LY231617（2,6 - 双（1,1 - 二甲基乙基）- 4 - [[（1 - 乙基）氨基]甲基]苯酚盐酸盐）在四动脉闭塞30分钟后给药的情况。
雄性Wistar大鼠接受30分钟的四动脉闭塞。LY231617要么在缺血前30分钟口服，要么在缺血开始30分钟后静脉注射。海马CA1层和纹状体损伤按0 - 3级评分（0，无损伤；3，细胞损失>90%）。我们还通过在LY231617存在的情况下，将原代培养的海马神经元暴露于50微摩尔浓度的过氧化氢中15分钟，评估LY231617预防铁依赖性脂质过氧化和预防过氧化氢诱导的海马神经元死亡的能力。
口服LY231617使纹状体和海马CA1损伤均减少>75%（p < 0.0001）。在两个独立实验中，LY231617在闭塞30分钟后开始静脉给药，在第一个实验中海马和纹状体损伤减少约50%（p < 0.03），在第二个实验中减少约41%（p < 0.02）。向原代海马神经元培养物中添加5微摩尔的LY231617可拮抗过氧化氢的致死作用（p < 0.05）。铁依赖性脂质过氧化也呈剂量依赖性受到抑制。
本研究中观察到LY231617能显著减轻缺血诱导或过氧化氢诱导的神经元损伤并抑制脂质过氧化，这表明活性氧中间体在全脑缺血/再灌注后导致神经元死亡的事件中起重要作用。
