NS 1231, a novel compound with neurotrophic-like effects in vitro and in vivo
NS 1231, a novel compound with neurotrophic-like effects in vitro and in vivo
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DOI：
10.1046/j.1471-4159.2002.00803.x
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发表时间：
2002-04-01
影响因子：
4.7
通讯作者：
Gronborg, M
中科院分区：
文献类型：
--
作者：
Dago, L;Bonde, C;Gronborg, M
NS 1231 [5-(4-氯苯基)-6,7,8,9-四氢-1H-吡咯并-[3.2-h]萘-2,3-二酮-3-肟]属于化学系列化合物，具有神经营养样活性。在体外，NS 1231 挽救了神经生长因子 (NGF) 分化的 PC12 细胞，使其免于因营养因子撤除而导致的死亡。此外，NS 1231 还能刺激未分化 PC12 细胞的包含 NGF 的神经突生长。在分子水平上，NS 1231 增强了 NGF 诱导的信号转导事件，例如 Shc 结合位点 Tyr490 处的 TrkA 磷酸化以及 PC12 细胞中的 ERK 激活。此外，NS 1231 还可降低器官型海马切片培养物中 NMDA 诱导的兴奋性毒性。在短暂性全身缺血的沙鼠模型中，NS 1231 治疗减少了海马 CA1 层神经元的延迟丢失。此外，NS 1231 治疗可使小鼠大脑中动脉闭塞 (MCAO) 模型的总梗塞体积减少 43%。因此，目前的数据表明 NS 1231 或结构类似物在治疗脑缺血方面具有治疗潜力。
NS 1231 [5-(4-chlorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo-[3.2-h]naphthalene-2,3-dione-3-oxime] belongs to a chemical series of compounds, which exhibit neurotrophic-like activities. In vitro, NS 1231 rescued nerve growth factor (NGF)-differentiated PC12 cells from death induced by withdrawal of trophic factors. In addition, NS 1231 stimulated NGF-incluced neurite outgrowth of undifferentiated PC12 cells. At the molecular level, NS 1231 enhanced NGF-induced signalling events, such as TrkA phosphorylation at the Shc-binding site Tyr490 as well as ERK activation in PC12 cells. Moreover, NS 1231 reduced NMDA-induced excitotoxicity in organotypic hippocampal slice cultures. In a gerbil model of transient global ischaemia, treatment with NS 1231 reduced the delayed loss of neurons in the hippocampal CA1 layer. Furthermore, NS 1231 treatment resulted in a 43% reduction in total infarct volume in the mouse middle cerebral artery occlusion (MCAO) model. The present data thus implicate a therapeutic potential of NS 1231 or structural analogues in treatment of cerebral ischaemia.