Monotherapy with dextromethorphan or tirilazad - but not a combination of both - improves outcome after transient focal cerebral ischemia in rats
Monotherapy with dextromethorphan or tirilazad - but not a combination of both - improves outcome after transient focal cerebral ischemia in rats
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DOI：
10.1007/s002210050498
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发表时间：
1998-09-01
影响因子：
2
通讯作者：
Reulen, HJ
中科院分区：
文献类型：
--
作者：
Schmid-Elsaesser, R;Zausinger, S;Reulen, HJ
脑缺血后的细胞死亡是由兴奋性氨基酸的大量释放，自由基的产生，以及-关键的一步-钙流入细胞所介导的。我们验证了一种假说，即通过不同的机制同时给予改善脑损伤的药物会产生协同的神经保护作用。采用大鼠短暂性局灶性脑缺血模型，研究了两种临床用药--N-甲基-D-天冬氨酸、钙通道拮抗剂右美沙芬(DM)和抗氧化剂替拉扎单用及联合用药的神经保护作用。雄性SD大鼠采用线栓法制作大脑中动脉闭塞90min模型。动物被随机分配到四个处理之一(n=10)：(1)赋形剂对照组，(2)DM，(3)替拉扎德，(4)DM+替利拉扎德。于缺血前15分钟及再灌流时分别给予药物或药物或载体。连续激光多普勒血流仪记录双侧局部脑血流量(LCBF)。通过日常神经学检查对功能缺陷进行量化。7天后对脑梗塞体积进行平面测量。DM可预防缺血后低灌注量。替拉扎德对下丘脑血流量无影响。DM或替拉扎单用可改善神经功能，使脑梗塞体积分别减少45%和48%。联合治疗未能影响神经功能恢复和脑梗塞体积。尽管从药理学的角度来看，右美沙芬和替拉扎德联合应用可能会导致相互抑制或加重不良反应，但可能会产生协同的神经保护作用。
Cell death after cerebral ischemia is mediated by a massive release of excitatory amino acids, generation of free radicals, and - a crucial step - calcium influx into cells. We examined the hypothesis that concurrent administration of drugs ameliorating brain damage via different mechanisms would result in a synergistic neuroprotective effect. The neuroprotective efficacy of two clinically available drugs - the N-methyl-D-aspartate and calcium-channel antagonist dextromethorphan (DM) and the antioxidant tirilazad - were studied in monotherapy and in combination in a rat model of transient focal ischemia. Male Sprague-Dawley rats were subjected to 90 min of middle-cerebral-artery occlusion by an intraluminal filament technique. The animals were randomly assigned to one of four treatments (n = 10 each): (1) vehicle-treated controls, (2) DM, (3) tirilazad, (4) DM+tirilazad. Drugs or vehicles were administered 15 min before ischemia and at reperfusion. Local cerebral blood flow (LCBF) was bilaterally recorded by continuous laser Doppler flowmetry. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed planimetrically after 7 days. DM prevented post-ischemic hypoperfusion. Tirilazad did not influence LCBF. Monotherapy with DM or tirilazad improved neurological function and reduced infarct volume by 45% and 48%, respectively. Combination therapy failed to influence neurological recovery and infarct volume. Although, from pharmacological point of view, a synergistic neuroprotective effect is expected, combination of dextromethorphan and tirilazad may lead to mutual inhibition or potentiate adverse effects.