Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries | Zendy

Changiz Taghibiglou | Zendy; Henry G. S. Martin | Zendy; Ted Weita Lai | Zendy; Taesup Cho | Zendy; Shiv S. Prasad | Zendy; Luba Kojic | Zendy; Jie Lu | Zendy; Yitao Liu | Zendy; Edmund Lo | Zendy; Shu Zhang | Zendy; Julia M. Wu | Zendy; Yu Ping Li | Zendy; Yan Wen | Zendy; Joon-Hyuk Imm | Zendy; Max Cynader | Zendy; Yu Tian Wang | Zendy

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

Author(s) -

Changiz Taghibiglou,

Henry G. S. Martin,

Ted Weita Lai,

Taesup Cho,

Shiv S. Prasad,

Luba Kojic,

Jie Lu,

Yitao Liu,

Edmund Lo,

Shu Zhang,

Julia M. Wu,

Yu Ping Li,

Yan Wen,

Joon-Hyuk Imm,

Max Cynader,

Yu Tian Wang

Publication year - 2009

Publication title -

nature medicine

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 19.536

H-Index - 547

eISSN - 1546-170X

pISSN - 1078-8956

DOI - 10.1038/nm.2064

Subject(s) - nmda receptor , neuroprotection , glutamate receptor , sterol regulatory element binding protein , excitotoxicity , receptor , chemistry , neuroscience , stroke (engine) , pharmacology , microbiology and biotechnology , biology , transcription factor , biochemistry , gene , mechanical engineering , engineering

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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