Verweij B H, Muizelaar J P, Vinas F C, Peterson P L, Xiong Y, Lee C P
Department of Neurosurgery, University of California at Davis Medical Center, Sacramento 95817, USA.
J Neurosurg. 2000 Nov;93(5):829-34. doi: 10.3171/jns.2000.93.5.0829.
Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats.
Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose.
The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.
确定用于实验性创伤性脑损伤（TBI）的一种药物的疗效，需要使用一种或多种结果指标，如降低死亡率或减少神经和神经心理缺陷。不幸的是，这些测试组合中的结果具有相当大的变异性，需要相对较大的样本量，而且测试本身的实施也非常耗时。作者先前证明，实验性TBI和人类TBI会诱导线粒体功能障碍。由于与神经行为终点相比，线粒体功能障碍易于评估，因此在临床前药物测试中，它可能作为一种结果指标来确定治疗时间窗和剂量反应曲线。这个想法在大鼠TBI模型中进行了测试。
在皮质撞击后用选择性N型电压敏感性钙通道阻滞剂齐考诺肽（也称为SNX-111和CI-1009）治疗的动物，脑线粒体功能有显著改善。当在从损伤前15分钟到损伤后10小时的不同时间间隔给予单次静脉推注4mg/kg齐考诺肽时，在所有时间点线粒体功能均得到改善，但在损伤后2至6小时改善更为明显。作者在损伤后4小时给予0.5至6mg/kg的单次推注，评估了不同剂量齐考诺肽对线粒体功能的影响，发现4mg/kg是最佳剂量。
作者基于线粒体结果指标，在总共42只大鼠中建立了这些时间窗概况和剂量反应曲线，因为这些测试中的标准差很低。通过使用神经行为终点来建立类似的时间窗概况和剂量反应曲线，在更复杂的实验中需要使用114只大鼠。
