Hao Jiukuan, Mdzinarishvili Alexander, Abbruscato Thomas J, Klein Jochen, Geldenhuys Werner J, Van der Schyf Cornelis J, Bickel Ulrich
Department of Pharmaceutical Sciences and PATOS Stroke Research Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
Brain Res. 2008 Feb 27;1196:113-20. doi: 10.1016/j.brainres.2007.11.075. Epub 2008 Jan 29.
The effect of the polycyclic cage amine NGP1-01, a dual action antagonist at both L-type calcium channels and NMDA receptors, was measured after transient (1 h) focal cerebral ischemia in the mouse middle cerebral artery occlusion (MCAO) model. Mice were left untreated, or received NGP1-01 (20 mg/kg per dose intraperitoneally), memantine (20 mg/kg per dose intraperitoneally), or vehicle (DMSO) at 15 min, 24 h and 48 h after reperfusion. Sensorimotor function was tested daily for two weeks using the "corner test", a proven paradigm for the assessment of functional integrity in rodents. NGP1-01 significantly reduced sensorimotor deficits over the 2-week period (p<0.001, ANOVA). Although memantine was less effective than NGP1-01 (p<0.05), it still significantly attenuated sensorimotor deficits in the animals. In a separate study, brain damage 3 days after stroke was determined histologically in mice receiving no treatment, DMSO, or NGP1-01 (dosages and dosage schedule same as above). Serial brain sections were stained for nonviable neurons with Fluoro-Jade B and the volume of damaged tissue was estimated. NGP1-01 treated mice had a significantly lower volume of brain damage (13+/-7 mm(3), p<0.01) than both control groups (no treatment: 47+/-4 mm(3), DMSO: 50+/-10 mm(3)). In conclusion, at weight-equivalent doses, NGP1-01 was at least as neuroprotective as the established NMDA receptor antagonist memantine. It may be a promising lead structure for the development of novel multiple-action drugs in treating ischemic stroke and other neurodegenerative diseases with an excitotoxic component.
在小鼠大脑中动脉闭塞（MCAO）模型短暂性（1小时）局灶性脑缺血后，测定了多环笼状胺NGP1-01（一种L型钙通道和NMDA受体的双重作用拮抗剂）的效果。小鼠未接受治疗，或在再灌注后15分钟、24小时和48小时接受NGP1-01（每剂量20mg/kg腹腔注射）、美金刚（每剂量20mg/kg腹腔注射）或溶剂（二甲基亚砜）。使用“角落试验”（一种用于评估啮齿动物功能完整性的成熟范式），连续两周每天测试感觉运动功能。在两周期间，NGP1-01显著减少了感觉运动缺陷（p<0.001，方差分析）。尽管美金刚的效果不如NGP1-01（p<0.05），但它仍显著减轻了动物的感觉运动缺陷。在另一项研究中，对未接受治疗、二甲基亚砜或NGP1-01（剂量和给药方案同上）的小鼠进行组织学检查，确定中风后3天的脑损伤情况。用Fluoro-Jade B对连续脑切片进行非存活神经元染色，并估计受损组织的体积。与两个对照组（未治疗：47±4mm³，二甲基亚砜：50±10mm³）相比，接受NGP1-01治疗的小鼠脑损伤体积显著更低（13±7mm³，p<0.01）。总之，在等效剂量下，NGP1-01的神经保护作用至少与已确立的NMDA受体拮抗剂美金刚相当。它可能是开发用于治疗缺血性中风和其他具有兴奋性毒性成分的神经退行性疾病的新型多作用药物的有前景的先导结构。
