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Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke.

Abstract
Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme gamma-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis, and by activating microglial cells and stimulating the infiltration of proinflammatory leukocytes. These findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions.
AuthorsThiruma V Arumugam, Sic L Chan, Dong-Gyu Jo, Gokhan Yilmaz, Sung-Chun Tang, Aiwu Cheng, Marc Gleichmann, Eitan Okun, Vishwa D Dixit, Srinivasulu Chigurupati, Mohamed R Mughal, Xin Ouyang, Lucio Miele, Tim Magnus, Suresh Poosala, D Neil Granger, Mark P Mattson
JournalNature medicine (Nat Med) Vol. 12 Issue 6 Pg. 621-3 (Jun 2006) ISSN: 1078-8956 [Print] United States
PMID16680150 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Enzyme Inhibitors
  • Notch1 protein, mouse
  • Peptides
  • Receptor, Notch1
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
Topics
  • Amyloid Precursor Protein Secretases
  • Animals
  • Apoptosis
  • Aspartic Acid Endopeptidases (antagonists & inhibitors, genetics, metabolism)
  • Brain (cytology, metabolism, pathology)
  • Brain Ischemia (metabolism, pathology, therapy)
  • Cells, Cultured
  • Endopeptidases (genetics, metabolism)
  • Enzyme Inhibitors (metabolism)
  • Humans
  • Leukocytes (metabolism)
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microglia (metabolism)
  • Neurons (cytology, metabolism)
  • Peptides (genetics, metabolism)
  • Rats
  • Receptor, Notch1 (genetics, metabolism)
  • Reperfusion Injury
  • Signal Transduction (physiology)
  • Stroke (metabolism, pathology, therapy)
  • Treatment Outcome

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