Moyanova Slavianka Georgieva, Kortenska Lidia Vasileva, Mitreva Rumiana Gesheva, Pashova Vyara Dincova, Ngomba Richard Teke, Nicoletti Ferdinando
Department of Neurobiology of Adaptation, Laboratory of Integrative Neuropharmacology, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Brain Res. 2007 Jun 11;1153:58-67. doi: 10.1016/j.brainres.2007.03.070. Epub 2007 Mar 28.
Transient focal ischemia produced by local infusion of endothelin-1 (ET1) in the territory of the middle cerebral artery has been proposed as a potentially useful model for the screening of drugs developed for the treatment of thrombo-embolic stroke. However, most of the data rely exclusively on the assessment of the infarct volume, which is only a partial predictor of the neurological outcome of stroke. Here, we have validated the model using a multimodal approach for the assessment of neuroprotection, which includes (i) determination of the infarct volume by 2,3,5-triphenyltetrazolium chloride staining; (ii) an in-depth behavioral analysis of the neurological deficit; and (iii) an EEG analysis of electrophysiological abnormalities in the peri-infarct somatosensory forelimb cortical area, S1FL. The non-competitive NMDA receptor antagonist, MK-801 (3 mg/kg, injected i.p. 20 min after ET1 infusion in conscious rats) could reduce the infarct volume, reverse the EEG changes occurring at early times post-ET1, and markedly improve the neurological deficit in ischemic animals. The latter effect, however, was visible at day 3 post-ET1, because the drug itself produced substantial behavioral abnormalities at earlier times. We conclude that a multimodal approach can be applied to the ET1 model of focal ischemia, and that MK-801 can be used as a reference compound to which the activity of safer neuroprotective drugs should be compared.
通过在大脑中动脉区域局部注入内皮素-1（ET1）产生的短暂性局灶性缺血，已被提议作为一种潜在有用的模型，用于筛选开发用于治疗血栓栓塞性中风的药物。然而，大多数数据仅依赖于梗死体积的评估，而梗死体积只是中风神经学结果的部分预测指标。在此，我们使用多模态方法验证了该模型用于评估神经保护作用，该方法包括：（i）通过2,3,5-三苯基氯化四氮唑染色确定梗死体积；（ii）对神经功能缺损进行深入的行为分析；以及（iii）对梗死周围体感前肢皮质区域S1FL的电生理异常进行脑电图分析。非竞争性NMDA受体拮抗剂MK-801（3mg/kg，在清醒大鼠中ET1注入后20分钟腹腔注射）可减少梗死体积，逆转ET1后早期出现的脑电图变化，并显著改善缺血动物的神经功能缺损。然而，后一种作用在ET1后第3天可见，因为该药物本身在早期会产生明显的行为异常。我们得出结论，多模态方法可应用于局灶性缺血的ET1模型，并且MK-801可作为一种参考化合物，与更安全的神经保护药物的活性进行比较。
