Permanent rescue of lesioned neonatal motoneurons and enhanced axonal regeneration by adenovirus-mediated expression of glial cell-line-derived neurotrophic factor.
Axotomy of peripheral nerves in neonatal rats induces motoneuron death that can be delayed but not arrested by the application of several neurotrophic factors (NFs) or adenoviral vectors carrying genes for NFs. We tested whether an adenoviral vector carrying the gene for glial cell-line-derived neurotrophic factor (Adv.RSV-GDNF) would prevent neonatal motoneuron death after facial nerve transection or crush. Nerve transection eliminates the pathway for axonal regeneration, while nerve crush preserves the pathway necessary for target reinnervation that may be required for the permanent rescue of motoneurons. Both types of injury cause substantial motoneuron death in neonatal animals. Adv.RSV-GDNF or a control vector carrying the beta-galactosidase gene (Adv.RSV-betagal) was injected into facial muscles 2 days before the nerve was transected, or Adv.RSV-GDNF, Adv.RSV-betagal, Adv.d1312 (a vector lacking a transgene), or vehicle was injected into facial muscles immediately after nerve crush. Four weeks after nerve transection, few motoneurons survived after Adv.RSV-GDNF and Adv.RSV-betagal treatment (6.1% and 2.4%, respectively). Four weeks after nerve crush, 40% of the motoneurons survived after Adv.RSV-GDNF treatment but only 17% survived in control groups. By 20 weeks, 39% of the motoneurons of the Adv.RSV-GDNF treatment groups survived but only 15-19% survived in controls. The numbers of myelinated axons of the buccal nerve branch of Adv.RSV-GDNF treatment groups were also higher than controls at 4 and 20 weeks (24% and 100% compared to 4.4-6.2% and 25-33% for Adv.RSV-GDNF and controls, respectively). By 20 weeks, Adv.RSV-GDNF-treated animals recovered 50% of the contralateral vibrissal function, while in controls only 5-11% of function was restored.
Baumgartner
B J
BJ
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA. brianb@bcm.tmc.edu
Shine
H D
HD
D000256:Adenoviridae; D000818:Animals; D000831:Animals, Newborn; D005152:Facial Muscles / Q000502:physiology; D005154:Facial Nerve / Q000187:drug effects / Q000254:growth & development; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009409:Nerve Crush; D009414:Nerve Growth Factors; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D001616:beta-Galactosidase / Q000008:administration & dosage / Q000235:genetics
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D001616:beta-Galactosidase