Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries.
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.
Taghibiglou
Changiz
C
Department of Medicine, Coastal Health Research Institute, University of British Columbia, Brain Research Centre, Vancouver, Canada.
Martin
Henry G S
HG
Lai
Ted Weita
TW
Cho
Taesup
T
Prasad
Shiv
S
Kojic
Luba
L
Lu
Jie
J
Liu
Yitao
Y
Lo
Edmund
E
Zhang
Shu
S
Wu
Julia Z Z
JZ
Li
Yu Ping
YP
Wen
Yan Hua
YH
Imm
Joon-Hyuk
JH
Cynader
Max S
MS
Wang
Yu Tian
YT
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*
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