The influence of GDNF on the timecourse and extent of motoneuron loss in the cervical spinal cord after brachial plexus injury in the neonate.

Injuries of the peripheral nerve in the early post-natal period are known to cause massive loss in the motoneuron pools of the spinal cord. However, the exact time frame and extent of motoneuron death in the cervical spinal cord after a brachial plexus lesion and the altered course after neuroprotection with different trophic factors is not known. In the present study, the time course of induced motoneuron death after a neonatal peripheral nerve injury and the effect of GDNF was investigated over a 4 week time period to determine the window of opportunity for possible therapeutic interventions in obstetrical plexus palsy. The brachial plexus of a total of 70 animals was explored within 12 hours after birth and divided at trunc level. The plexus was then labeled with a fluorescent tracer to identify the corresponding motoneuron pool. Two groups were prepared: Group I remained untreated to assess the natural course of induced neuronal death. Group II received GDNF immediately after the lesion. Post-operatively the animals were evaluated sequentially over 29 days. Surviving motoneurons were evaluated quantitatively counting the nucleoli. The entire brachial plexus of the rat is supplied by a total of about 4000 motoneurons. After injury the number of motoneurons steadily diminished within the first 10 days to reach a plateau of about 20% of the original number. At this time the GDNF treated group still had 85% (3330 +/- 247) of motoneurons viable. This further decreased so that at the termination of the experiment at day 29 there were still 2527 +/- 285 motoneurons alive. This study clearly shows that pathology after a brachial plexus injury in the newborn is not restricted to the peripheral nerve alone. In this model 64% of motoneurons underwent apoptosis within the first week after injury, reaching a plateau after 10 days at 20%. GDNF successfully rescued motoneurons so that after 4 weeks still 65% were present. We conclude that GDNF leads to enhanced motoneuron survival so that exogenous trophic support of motoneurons might have a role in the treatment of all types of severe neonatal plexopathies, maintaining the viability of motoneurons until reconstructive surgery provides them with a pathway for regeneration and endogenous trophic support.