Taghibiglou Changiz, Martin Henry G S, Lai Ted Weita, Cho Taesup, Prasad Shiv, Kojic Luba, Lu Jie, Liu Yitao, Lo Edmund, Zhang Shu, Wu Julia Z Z, Li Yu Ping, Wen Yan Hua, Imm Joon-Hyuk, Cynader Max S, Wang Yu Tian
Department of Medicine, Coastal Health Research Institute, University of British Columbia, Brain Research Centre, Vancouver, Canada.
Nat Med. 2009 Dec;15(12):1399-406. doi: 10.1038/nm.2064. Epub 2009 Nov 22.
Excitotoxic neuronal damage caused by overactivation of N-methyl-D-aspartate glutamate receptors (NMDARs) is thought to be a principal cause of neuronal loss after stroke and brain trauma. Here we report that activation of sterol regulatory element binding protein-1 (SREBP-1) transcription factor in affected neurons is an essential step in NMDAR-mediated excitotoxic neuronal death in both in vitro and in vivo models of stroke. The NMDAR-mediated activation of SREBP-1 is a result of increased insulin-induced gene-1 (Insig-1) degradation, which can be inhibited with an Insig-1-derived interference peptide (Indip) that we have developed. Using a focal ischemia model of stroke, we show that systemic administration of Indip not only prevents SREBP-1 activation but also substantially reduces neuronal damage and improves behavioral outcome. Our study suggests that agents that reduce SREBP-1 activation such as Indip may represent a new class of neuroprotective therapeutics against stroke.
N-甲基-D-天冬氨酸谷氨酸受体（NMDARs）过度激活所导致的兴奋性毒性神经元损伤被认为是中风和脑外伤后神经元丧失的主要原因。在此我们报告，在受影响的神经元中，固醇调节元件结合蛋白-1（SREBP-1）转录因子的激活是在体外和体内中风模型中NMDAR介导的兴奋性毒性神经元死亡的一个关键步骤。NMDAR介导的SREBP-1激活是胰岛素诱导基因-1（Insig-1）降解增加的结果，我们开发的一种源自Insig-1的干扰肽（Indip）可抑制这种降解。利用中风的局灶性缺血模型，我们表明全身给予Indip不仅可防止SREBP-1激活，还可显著减少神经元损伤并改善行为结果。我们的研究表明，诸如Indip这类可减少SREBP-1激活的药物可能代表了一类新型的抗中风神经保护疗法。
