PERMANENT RESCUE OF LESIONED NEONATAL MOTONEURONS AND ENHANCED AXONALREGENERATION 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 ne urotrophic factors (NFs) or adenoviral vectors carrying genes for NFs. We tested whether an adenoviral vector carrying the gene for glial ce ll-line-derived neurotrophic factor (Adv.RSV-GDNF) would prevent neona tal motoneuron death after facial nerve transection or crush, Nerve tr ansection eliminates the pathway for axonal regeneration, while nerve crush preserves the pathway necessary for target reinnervation that ma y be required for the permanent rescue of motoneurons. Both types of i njury cause substantial motoneuron death in neonatal animals, Adv.RSV- GDNF or a control vector carrying the beta-galactosidase gene (AdV.RSV -beta gal) was injected into facial muscles 2 days before the nerve wa s transected, or Adv.RSV-GDNF, Adv.RSV-beta gal, Adv.dl312 (a vector l acking a transgene), or vehicle was injected into facial muscles immed iately after nerve crush, Four weeks after nerve transection, few moto neurons survived after Adv.RSV-GDNF and Adv.RSV-beta gal treatment (6. 1% and 2.4%, respectively). Four weeks after nerve crush, 40% of the m otoneurons 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 hut 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 co ntrols, respectively), By 20 weeks, Adv.RSV-GDNF-treated animals recov ered 50% of the contralateral vibrissal function, while in controls on ly 5-11% of function was restored. J. Neurosci. Res. 54:766-777, 1998, (C) 1998 Wiley-Liss, Inc.