HSV-mediated transfer of artemin overcomes myelin inhibition to improve outcome after spinal cord injury.
Artemin is a neurotrophic factor of the glial cell line-derived neurotrophic factor (GDNF) family of ligands that acts through the GDNF family receptor alpha3 (GFRalpha3)/ret receptor found predominantly on sensory and sympathetic neurons. In order to explore the potential utility of artemin to improve functional outcome after spinal cord injury (SCI), we constructed a nonreplicating herpes simplex virus (HSV)-based vector to express artemin (QHArt). We found that QHArt efficiently transfects spinal cord neurons to produce artemin. Transgene-mediated artemin supported the extension of neurites by primary dorsal root ganglion neurons in culture, and allowed those cells to overcome myelin inhibition of neurite extension through activation of protein kinase A (PKA) to phosphorylate cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and increase expression of arginase I. Intraspinal injection of QHArt immediately after thoracic spinal cord dorsal over hemisection produced a statistically significant improvement in motor recovery over the course of four weeks measured by locomotor rating score.
Zhou
Zhigang
Z
Department of Neurology, University of Michigan, Ann Arbor, USA.
Peng
Xiangmin
X
Fink
David J
DJ
Mata
Marina
M
D000818:Animals; D001119:Arginase / Q000378:metabolism; D001369:Axons / Q000502:physiology; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D007120:Immunochemistry; D009185:Myelin Proteins / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics*; D013116:Spinal Cord / Q000166:cytology; D013119:Spinal Cord Injuries / Q000628:therapy*
C490887:Artn protein, rat; D002227:Carbazoles; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D011758:Pyrroles; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D001119:Arginase