Neuroprotection of glial cell line-derived neurotrophic factor in damaged spinal cords following contusive injury.
Glial cell line-derived neurotrophic factor (GDNF) acts as a potent survival factor for many neuronal populations, including spinal motoneurons, indicating the therapeutic promise of GDNF for neurological disorders. Injury to spinal cord (SCI) triggers processes destructive to ascending sensory and descending motor conduction and extends tissue loss, thereby leading to permanent behavioral dysfunction. In this study, we attempted to examine whether GDNF protects neurons from SCI and subsequently lessens locomotor deficit in SCI rats. We utilized the NYU weight-drop device developed at New York University to induce spinal cord contusion at the T9-10 spinal segment. After SCI, GDNF was administrated into the cord 1-2 mm rostral and caudal to the epicenter. Animals receiving GDNF treatment showed significant improvement over phosphate-buffered saline (PBS)-treated controls on the Basso Beattie Bresnahan (BBB) locomotor rating scale (P < 0.01-0.001). GDNF treatment increased the remaining neuronal fibers with calcitonin gene-related peptide, neurofilament, and growth-associated protein 43 immunoreactivity in injured spinal tissues compared with PBS-treated controls. Moreover, treatment with GDNF caused approximately 50% cell survival in the contused spinal cord tissues. Examination of signal transduction triggered by GDNF indicated that GDNF injection transiently induced activation of the mitogen-activated protein (MAP) kinase pathway in the spinal cord. Additionally, an up-regulation of anti-apoptotic Bcl-2 levels in the contusive center of the damaged spinal cord was observed 24 hr post-GDNF injection. Together our results show that GDNF exerts behavioral and anatomic neuroprotection following SCI. Additionally, GDNF-activated MAP kinase and Bcl-2 signaling may contribute to neuronal survival after spinal cord contusion.
Cheng
Henrich
H
Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taiwan.
Wu
Jey-Pei
JP
Tzeng
Shun-Fen
SF
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D003288:Contusions; D029721:Drosophila Proteins; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006614:Hindlimb; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009069:Movement Disorders / Q000188:drug therapy / Q000378:metabolism; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*
D029721:Drosophila Proteins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D020928:Mitogen-Activated Protein Kinases