Aim:Post-injury regeneration of peripheral nerves remains a challenge despite technological and surgical advancements such as nerve grafting or primary repair, and complete functional recovery is not possible. Uridine is the major pyrimidine nucleoside in circulation which has neuroprotective properties when administered exogenously. This study investigated the possible mediation of epigenetic mechanisms underlying the regenerative effect of uridine in a sciatic nerve transection rat model.Material and Methods:Fifty adult male rats were randomized to sham, control, and uridine groups. After unilateral transection and primary anastomosis of the right sciatic nerve, a single daily dose of saline (1 ml/kg; sham and control groups) or uridine (500 mg/kg; uridine group) was injected intraperitoneally for a week. The sciatic nerves were removed en bloc on the eighth day and levels of histone deacetylase 1 (HDAC1), acetylated histone-H3, and acetylated histone-H4 were analyzed in nerve homogenates. The number of myelinated axons in the sciatic nerve specimens was analyzed histomorphologically.Results:The HDAC1 levels were significantly greater in the control group than in the sham (p < 0.001) and uridine (p < 0.01) groups. Compared to the sham group, the acetylated histone-H3 and histone-H4 levels decreased in the control group (by 81.49% and 79.98%, respectively; p < 0.001) and increased significantly in the uridine group (p < 0.01, p < 0.05). The number of myelinated axons decreased significantly (p < 0.001) in the control group, which was enhanced significantly by uridine administration. Conclusion:Epigenetic mechanisms may partly mediate the regenerative effect of uridine treatment in a rat model of sciatic nerve injury. Our data provides novel insights in the management of peripheral nerve damage and suggests potential benefit of uridine for degenerative diseases in which epigenetic impairments are involved.