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.
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We thank J. Ye (University of Texas Southwestern Medical Center) for myc–Insig-1 plasmid, T. Osborne (University of California–Irvine) for Flag–nt-SREBP-1 and Y. P. Auberson (Novartis Pharma AG) for the generous gift of NVP-AAM077. We also thank J. Wang for his technical support. This work was supported by the Heart and Stroke Foundation of British Columbia and the Yukon, the Canadian Institutes of Health Research and CHDI (Cure Huntington's Disease Initiative) Foundation. Y.T.W. is a Howard Hughes Medical Institute International Scholar and Heart and Stroke Foundation of British Columbia and the Yukon Chair in Stroke Research. C.T. was supported by post-doctoral fellowships from the Canadian Institutes of Health Research and Michael Smith Foundation for Health.
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Taghibiglou, C., Martin, H., Lai, T. et al. Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Nat Med 15, 1399–1406 (2009). https://doi.org/10.1038/nm.2064
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