Netrin-1 attenuates ischemic stroke-induced apoptosis.
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.
Wu
T-W
TW
Institute of Molecular Biology, Academia Sinica, 128 Academia Road, Section 2, Nangang, Taipei, Taiwan 115.
Li
W-W
WW
Li
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000075389:DCC Receptor; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005452:Fluoresceins; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000187:drug effects; D009930:Organic Chemicals; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013778:Tetrazolium Salts; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000075389:DCC Receptor; D005452:Fluoresceins; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D000075388:Netrin-1; D009930:Organic Chemicals; D011956:Receptors, Cell Surface; D013778:Tetrazolium Salts; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C501910:Dcc protein, mouse; C000617353:Ntn1 protein, mouse; C435731:fluoro jade; C009591:triphenyltetrazolium; C000617307:Unc5b protein, mouse