丁基苯酞的药理作用及作用机制的研究
摘要
丁基苯酞(dl-3-n-butylphthalide，dl-NBP)是我们医科院药物研究所开发研制的抗脑缺血新药。L-NBP最初是自芹菜籽中分离提取的有效成分，现已由本所药物化学合成室人工合成了消旋体并拆分得到了其光学活性异构体d-NBP和l-NBP。经本组多年研究证实，dl-NBP可改善全脑缺血后脑能量代谢；缩小局灶性脑缺血后脑梗塞面积，减轻神经功能损伤症状：改善大脑中动脉阻断后纹状体血流量；保护局灶性脑缺血后动物的学习记忆功能。以往的研究只局限在对脑缺血的治疗。我们知道，脑缺血、缺氧、蛛网膜下腔出血、脑外伤往往引起相似的病理生理变化，dl-NBP对脑缺血的良好治疗效果提示它可能对蛛网膜下腔出血和脑外伤有一定的保护作用，为此，本实验初步研究了dl-NBP对大鼠蛛网膜下腔出血和小鼠闭合性脑外伤的作用。另外，脑缺血再灌注后会引起较单纯缺血更严重的脑损伤，为此对局灶性脑缺血再灌注后血脑屏障通透性的变化和脑水肿的形成及其药物的作用进行了探讨。以往对dl-NBP作用机制研究表明，dl-NBP对NOS-NO-CGMP系统、细胞内钙和脑能量代谢有一定的作用，本研究进一步探讨了dl-NBP的可能作用机理。丁基苯酞对蛛网膜下腔出血后局部脑血流的改善和对血脑屏障活性的影响
侧脑室注射自体动脉血造成大鼠蛛网膜下腔出血模型，氢清除法测定尾状核血流量。结果表明，侧脑室注血后15分钟，尾状核血流量即显著降低(约为正常的50％左右)，并在3小时内基本上维持在此水平。蛛网膜下腔出血后5分钟，给dl-NBP(50-100mg／kg，po或5-20 mg／kg，ip)可明显提高30～180分钟内尾状核血流量，而对平均动脉压无明显影响。实验结果还表明，d-NBP和l-NBP的作用存在明显差异，d-NBP(10mg／kg，ip)可明显提高蛛网膜下腔出血后尾核脑血流量，但同剂量的l-NBP对脑血流无明显影响。另外，dl-NBP 10mg／kg还可保护血脑屏障，降低蛛网膜下腔出血6小时后血脑屏障对血浆蛋白的通透性的增加。
丁基苯酞对小鼠闭合性脑外伤的保护作用
研究了dl-NBP对小鼠闭合性脑外伤24小时后脑损伤的保护作用，结果表明，脑外伤后24小时可引起小鼠记忆功能下降，跳台试验发现电刺激后跳台潜伏期明显延
Dl-3-n-butylphthalide(dl-NBP), a new anti-cerebral ischemic drug, is being developed by our institute. L-NBP, primary derived from the seed of celery and synthesized by the Department of Medicinal Chemistry of our Institute, has been shown to improve brain energy metabolism after global cerebral ischemia, to reduce the infarct volume, attenuate delayed neuronal damage after focal cerebral ischemia, and to improve regional cerebral blood flow in ischemic brain. However, its action mechanism has not been clarified to explain its actions. In addition, previous studies of dl-NBP were confined to cerebral ischemia, however, hypoxia, subarachnoid hemorrhage, neurotrauma and cerebral ischemia always appears to induce similar pathophysiological insult in brain. Therefore, the possible therapeutic action of dl-NBP on subarachnoid hemorrhage and the closed head injury, the protective effects on reperfusion-induced brain injury after cerebral ischemia, and its mechanisms were evaluated in the present study.
EFFECTS OF DL-NBP ON REGIONAL CEREBRAL BLOOD FLOW AND BLOOD-BRAIN BARRIER AFTER SUBARACHNOID HEMORRHAGE
Subarachnoid hemorrhage (SAH) was induced by injection of 0.35 ml autologous artery blood into lateral ventricle. Regional cerebral blood flow (rCBF)in caudate nucleus was determined by hydrogen clearance method. The results indicated that a rapid and marked decrease in rCBF in caudate nucleus was observed 15 min after SAH and the rCBF was remained at low level (about 50% pre-SAH value) within 180 min. Dl-NBP(50-100mg/kg, po) was shown to increase rCBF 30~180 min after the onset of SAH without significant effect on mean artery blood pressure. Dl-NBP (5-20 mg/kg, ip) was also shown to increase rCBF after SAH. The study also displayed that d-NBP but
侧脑室注射自体动脉血造成大鼠蛛网膜下腔出血模型，氢清除法测定尾状核血流量。结果表明，侧脑室注血后15分钟，尾状核血流量即显著降低(约为正常的50％左右)，并在3小时内基本上维持在此水平。蛛网膜下腔出血后5分钟，给dl-NBP(50-100mg／kg，po或5-20 mg／kg，ip)可明显提高30～180分钟内尾状核血流量，而对平均动脉压无明显影响。实验结果还表明，d-NBP和l-NBP的作用存在明显差异，d-NBP(10mg／kg，ip)可明显提高蛛网膜下腔出血后尾核脑血流量，但同剂量的l-NBP对脑血流无明显影响。另外，dl-NBP 10mg／kg还可保护血脑屏障，降低蛛网膜下腔出血6小时后血脑屏障对血浆蛋白的通透性的增加。
丁基苯酞对小鼠闭合性脑外伤的保护作用
研究了dl-NBP对小鼠闭合性脑外伤24小时后脑损伤的保护作用，结果表明，脑外伤后24小时可引起小鼠记忆功能下降，跳台试验发现电刺激后跳台潜伏期明显延
Dl-3-n-butylphthalide(dl-NBP), a new anti-cerebral ischemic drug, is being developed by our institute. L-NBP, primary derived from the seed of celery and synthesized by the Department of Medicinal Chemistry of our Institute, has been shown to improve brain energy metabolism after global cerebral ischemia, to reduce the infarct volume, attenuate delayed neuronal damage after focal cerebral ischemia, and to improve regional cerebral blood flow in ischemic brain. However, its action mechanism has not been clarified to explain its actions. In addition, previous studies of dl-NBP were confined to cerebral ischemia, however, hypoxia, subarachnoid hemorrhage, neurotrauma and cerebral ischemia always appears to induce similar pathophysiological insult in brain. Therefore, the possible therapeutic action of dl-NBP on subarachnoid hemorrhage and the closed head injury, the protective effects on reperfusion-induced brain injury after cerebral ischemia, and its mechanisms were evaluated in the present study.
EFFECTS OF DL-NBP ON REGIONAL CEREBRAL BLOOD FLOW AND BLOOD-BRAIN BARRIER AFTER SUBARACHNOID HEMORRHAGE
Subarachnoid hemorrhage (SAH) was induced by injection of 0.35 ml autologous artery blood into lateral ventricle. Regional cerebral blood flow (rCBF)in caudate nucleus was determined by hydrogen clearance method. The results indicated that a rapid and marked decrease in rCBF in caudate nucleus was observed 15 min after SAH and the rCBF was remained at low level (about 50% pre-SAH value) within 180 min. Dl-NBP(50-100mg/kg, po) was shown to increase rCBF 30~180 min after the onset of SAH without significant effect on mean artery blood pressure. Dl-NBP (5-20 mg/kg, ip) was also shown to increase rCBF after SAH. The study also displayed that d-NBP but
引文
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