Injuries to peripheral nerves can be very serious,resulting in severe muscle atrophy,while the consequences are more devas-tating when the injury also involves the central nervous system,such as avulsion injury.One common example in human is brachial plexus injury mostly involving the avulsion of spinal roots from the spinal cord,causing the motoneuron death in addition to the axonal injury to peripheral nerve.Due to the progressive motoneuron death and reduction in axonal regen-erative capability,the surgical repair should be done as soon as possible for best outcome,but unfortunately there is always a quite long delay in real clinical settings.So perhaps some other interventions could be used to help rescue motoneurons,enhance the axonal regeneration and prevent the muscle atrophy during regeneration.Glial cell line-derived neurotrophic factor (GDNF) has been shown to be able to help motoneuron survival,though its effects on regeneration have been studied less.Here we use C5-7 spinal root avulsion models that resemble the brachial plexus injury to seek whether GDNF treatment is able to help motoneurons to survive and regenerate when the surgical spinal root reimplantation is delayed.We hereby show that immediate GDNF treatment together with 2-week delayed root reimplantation helps ~72% of motoneurons to survive after 14 weeks of the injury,while only ~52% and 38% of motoneurons survive without the GDNF treatment after immediate or 2-week delayed reimplantation,respectively.In GDNF treatment group,we are also able to see slightly more retrogradely labeled motoneurons (267 ± 126) that have regenerated their axons along the nerve compared with the group without GDNF treatment (95 ± 94).In contrast,Terzis grooming test and electromyographic studies do not show any earli-er functional recovery in GDNF treated group compared with the group without GDNF treatment.However,2-week delay in spinal root reimplantation compared with the immediate root reimplantation causes extra 10% weight drop (from 54% to 45%) that can be prevented by GDNF treatment before the delayed reimplantation.However,the muscle atrophy is still severe after this long regeneration time and might be the reason for the poor functional outcome.Therefore,cell transplan-tation will be next used in this model together with the GDNF treatment.The underlying reason is that the transplantation of rat embryonic spinal cord fetal cells into the transected musculocutaneous nerve close to the muscle entering site helps to prevent the target muscle atrophy shown by increased muscle weight (from 43% to 69%) and muscle fiber area (from 31% to 70%) at 12 weeks after the injury as we have previously shown.These cells are seen to extend their axons along the nerve and form new functional connections with the muscle endplates,resulting in reduced atrophy.Therefore,combination strategy of GDNF treatment for motoneuron survival and potentially for regeneration together with cell therapy for muscle atrophy prevention should be considered next.