Tsuchida E, Harms J F, Woodward J J, Bullock R
Department of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
J Neurosurg. 1996 Jul;85(1):104-11. doi: 10.3171/jns.1996.85.1.0104.
Acute subdural hematoma kills or disables more severely head injured patients than any other complication of cranial trauma. The main pathological factor involved is ischemic neuronal damage, which is caused by raised intracranial pressure and local effect. The authors have evaluated the hypothesis that a novel use-dependent sodium channel antagonist, 619C89, could reduce ischemic brain damage in the rat subdural hematoma model. Because previous studies have shown that focal neuronal damage may be mediated by "excitotoxic" mechanisms, and because excitatory amino acid levels have been shown to be markedly elevated after brain trauma in humans, the authors have measured levels of glutamate, aspartate, and threonine within the cortex underneath the hematoma, using in vivo microdialysis before and after induction of hematoma, in both vehicle- and drug-treated rats. Postinjury treatment with 619C89 (30 mg/kg) significantly reduced the volume of hemispheric ischemic damage produced by subdural hematoma, from 99.77 +/- 7.51 mm3 in vehicle-treated control rats to 46.07 +/- 11.06 mm3 (p = 0.0007) in drug-treated animals. In the vehicle-treated animals, induction of subdural hematoma led to a fourfold increase in glutamate in the first 30 minutes after subdural hematoma occurred. The mean extracellular glutamate concentration in these animals remained 2- to 2.6-fold increased over the following 2.5 hours. In the 619C89-treated animals, the release of glutamate from the cortex underneath the hematoma was significantly attenuated. In these rats, induction of subdural hematoma led to a 2.7-fold increase in the first 30-minute sample, but extracellular glutamate concentration returned to near-basal levels thereafter, compared with vehicle-treated animals (p < 0.05). These results show that 619C89 is highly neuroprotective in this model and that its effects may, in part, be mediated by the inhibition of glutamate release from the ischemic cortex underneath the hematoma.
急性硬膜下血肿比颅脑创伤的任何其他并发症导致更多严重颅脑损伤患者死亡或致残。主要的病理因素是缺血性神经元损伤，这是由颅内压升高和局部效应引起的。作者评估了一种新型的使用依赖性钠通道拮抗剂619C89可减少大鼠硬膜下血肿模型中缺血性脑损伤的假说。因为先前的研究表明局灶性神经元损伤可能由“兴奋性毒性”机制介导，并且因为在人类脑外伤后兴奋性氨基酸水平已被证明显著升高，作者在血肿诱导前后，使用体内微透析法测量了在接受载体和药物治疗的大鼠血肿下方皮质内谷氨酸、天冬氨酸和苏氨酸的水平。用619C89（30mg/kg）进行损伤后治疗显著减少了硬膜下血肿产生的半球缺血性损伤体积，从接受载体治疗的对照大鼠中的99.77±7.51mm³降至接受药物治疗动物中的46.07±11.06mm³（p = 0.0007）。在接受载体治疗的动物中，硬膜下血肿诱导导致硬膜下血肿发生后的最初30分钟内谷氨酸增加了四倍。在接下来的2.5小时内，这些动物的细胞外谷氨酸平均浓度保持在升高2至2.6倍的水平。在接受619C89治疗的动物中，血肿下方皮质中谷氨酸的释放显著减弱。在这些大鼠中，硬膜下血肿诱导导致最初30分钟样本中增加了2.7倍，但此后细胞外谷氨酸浓度与接受载体治疗的动物相比恢复到接近基础水平（p < 0.05）。这些结果表明619C89在该模型中具有高度神经保护作用，并且其作用可能部分是通过抑制血肿下方缺血皮质中谷氨酸的释放来介导的。
