Netrin-1 attenuates ischemic stroke-induced apoptosis.

Abstract

In the present study we tested the protective effects of netrin-1 in stroke and investigated the potential underlying mechanisms. When we performed middle cerebral artery occlusion (MCAO) on adult mice, up-regulation of the receptor uncoordinated gene 5H2 (UNC5H2) but not its ligand netrin-1 was detected with RT-PCR and immunohistochemistry. Injection of netrin-1, 1 day after MCAO, significantly reduced infarct volume at 3 days after MCAO as revealed by functional magnetic resonance imaging. The ischemic cortex was preserved when netrin-1 was continuously administered. Fluoro-Jade and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling staining showed that netrin-1 reduced the number of dying neurons and apoptotic cells after MCAO. Ischemia-induced p53 expression was attenuated by netrin-1. We also tested the ability of netrin-1 to attract intrinsic neuronal stem cells to the infarct area. Both DCC and UNC5H2 were expressed in neurosphere culture and netrin-1 attracted stem cells in an in vitro transwell assay. However, in vivo netrin-1 administration did not enhance the MCAO-induced stem cell migration toward the infarct area. Our study shows that UNC5H2 expression was elevated after MCAO and administration of netrin-1 protected infarct tissue from p53-mediated apoptosis. These data indicate that the p53/dependent receptor pathway is involved in ischemic stroke pathology and suggest possible new stroke therapies.

• Authors: T-W Wu, W-W Li, H Li
• Journal: Neuroscience (Neuroscience) Vol. 156 Issue 3 Pg. 475-82 (Oct 15 2008) ISSN: 0306-4522 [Print] United States
• PMID: 18786616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DCC Receptor
• Dcc protein, mouse
• Fluoresceins
• Nerve Growth Factors
• Netrin Receptors
• Ntn1 protein, mouse
• Organic Chemicals
• Receptors, Cell Surface
• Tetrazolium Salts
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Unc5h2 protein, mouse
• fluoro jade
• Netrin-1
• triphenyltetrazolium

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Brain Infarction (drug therapy, etiology, pathology)
• Cell Movement (drug effects)
• Cells, Cultured
• Cerebral Cortex (cytology)
• DCC Receptor
• Disease Models, Animal
• Embryo, Mammalian
• Fluoresceins
• In Situ Nick-End Labeling (methods)
• Infarction, Middle Cerebral Artery (drug therapy, physiopathology)
• Magnetic Resonance Imaging
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Growth Factors (genetics, metabolism, pharmacology)
• Netrin Receptors
• Netrin-1
• Neurons (drug effects)
• Organic Chemicals
• Receptors, Cell Surface (genetics, metabolism)
• Tetrazolium Salts
• Tumor Suppressor Protein p53 (metabolism)
• Tumor Suppressor Proteins (genetics, metabolism, pharmacology)
• Up-Regulation (drug effects, physiology)