Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries

• Published in: Nature medicine Vol. 15; no. 12; pp. 1399 - 1406
• Main Authors: Wang, Yu Tian, Cho, Taesup, Prasad, Shiv, Li, Yu Ping, Lu, Jie, Lai, Ted Weita, Cynader, Max S, Lo, Edmund, Taghibiglou, Changiz, Kojic, Luba, Zhang, Shu, Imm, Joon-Hyuk, Wen, Yan Hua, Wu, Julia Z Z, Martin, Henry G S, Liu, Yitao
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2009; Nature Publishing Group
• Subjects: Animals; Binding sites; Biomedical and Life Sciences; Biomedicine; Brain Ischemia - physiopathology; Cancer Research; Care and treatment; Cell Line; Cell receptors; Cells, Cultured; Cerebral Cortex - blood supply; Disease Models, Animal; Genetic aspects; Health aspects; Humans; Infectious Diseases; Insulin; Intracellular Signaling Peptides and Proteins; Membrane Proteins - physiology; Metabolic Diseases; Molecular Medicine; Nervous system diseases; Neurons; Neurosciences; Peptides; Proteins; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - physiology; Sterol Regulatory Element Binding Protein 1 - physiology; Stroke (Disease); Toxicity; Transcription factors; China
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2064

Excitotoxicity mediated by over activation of glutamate receptors results in neuronal loss after ischemia. Activation of sterol regulatory element–binding protein-1 is now shown to be crucial for glutamate-mediated excitotoxic neuronal death in a mouse model of stroke. 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.