Damage to peripheral nerves often results in various sensory and motor abnormalities.The loss of neurotrophic factor support has been proposed to contribute to the development of peripheral neuropathy.The main objective of this research is to investigate the role of GDNF deficiency and protective effect using peripheral gene delivery in a rat model of constriction-induced peripheral nerve injury (CCI).We began by defining chronologically the molecular events and behavioral changes that occur after inducing CCI in a rodent model of peripheral nerve injury.This was followed by evaluation of the therapeutic effect of GDNF gene delivery via intramuscular route and measuring its outcome using immunohistological and molecular methods.It was shown that the mechanical and thermal hypersensitivity increased on the injured side at day 7 after induced CCI.These neurological changes were found to correlate to the structural changes in the sciatic nerve after injury.GDNF gene delivery was effective in the restoration of GDNF content, and hence, downstream Akt signalling pathway, an important pro-survival signal for nerves.These, in turn, prevent the loss of Schwann cells and axon fibers in peripheral nerves after constriction-injury insults.Most importantly, histological improvements were accompanied by a significant improvement in behavioural assessment.Our study showed for the first time that a single IM injection of Ad-GDNF improved the histological features of axonal damage in the sciatic nerve after CCI.GDNF and down-stream molecules hold promising potential as therapeutic targets in peripheral nerve injury.