Netrin-1 attenuates ischemic stroke-induced apoptosis

• Published in: Neuroscience 2008-10, Vol.156 (3), p.475-482
• Main Authors: Wu, T.-W, Li, W.-W, Li, H
• Format: Article
• Language: English
• Subjects: Animals; anti-apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Brain Infarction - drug therapy; Brain Infarction - etiology; Brain Infarction - pathology; Cell Movement - drug effects; Cells, Cultured; Cerebral Cortex - cytology; DCC Receptor; dependence receptor; Disease Models, Animal; Embryo, Mammalian; Fluoresceins; Fundamental and applied biological sciences. Psychology; In Situ Nick-End Labeling - methods; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - physiopathology; ischemia; Magnetic Resonance Imaging; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Nerve Growth Factors - pharmacology; Netrin Receptors; Netrin-1; Neurology; Neurons - drug effects; Organic Chemicals; p53; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Tetrazolium Salts; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - pharmacology; UNC5H2; Up-Regulation - drug effects; Up-Regulation - physiology; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.08.015

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.