title: Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries.
abstract: 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.
authors: Department of Medicine, Coastal Health Research Institute, University of British Columbia, Brain Research Centre, Vancouver, Canada.
authors: Changiz
authors: C
authors: Taghibiglou
authors: Henry G S
authors: HG
authors: Martin
authors: Ted Weita
authors: TW
authors: Lai
authors: Taesup
authors: T
authors: Cho
authors: Shiv
authors: S
authors: Prasad
authors: Luba
authors: L
authors: Kojic
authors: Jie
authors: J
authors: Lu
authors: Yitao
authors: Y
authors: Liu
authors: Edmund
authors: E
authors: Lo
authors: Shu
authors: S
authors: Zhang
authors: Julia Z Z
authors: JZ
authors: Wu
authors: Yu Ping
authors: YP
authors: Li
authors: Yan Hua
authors: YH
authors: Wen
authors: Joon-Hyuk
authors: JH
authors: Imm
authors: Max S
authors: MS
authors: Cynader
authors: Yu Tian
authors: YT
authors: Wang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply*; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology*
chemical_list: C491574:Insig1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1