Uridine Improves Locomotor Activity and Sciatic Nerve Integrity in a Mouse Model of Diabetes Mellitus

Diabetic peripheral neuropathy is an important cause of functional disability, and current therapies have limited ability to halt its progression. Uridine, a pyrimidine nucleoside essential for the synthesis of membrane phospholipids and neuronal metabolism, appears to be a potential neuroprotective agent, but its impact on motor behavior and peripheral nerve integrity in diabetes remains insufficiently investigated. Our study investigated the effects of chronic uridine supplementation on locomotor performance, neuromuscular electrophysiological manifestations, and morphological changes in the sciatic nerve in a murine model of streptozotocin-induced diabetes. We used male C57BL/6 mice (n = 8/group) that were assigned to three groups: sham (no diabetes), diabetic (streptozotocin-induced, diabetes mellitus, DM+), and diabetic treated with uridine (DM+U). We observed that uridine did not alter the metabolic status, as the HbA1c values remained comparable between diabetic groups (9.93 ± 0.57% DM+ vs. 9.71 ± 0.55% DM+U; p = 0.72), suggesting effects independent of glycemic control. The open field test revealed that diabetic mice showed a marked reduction in spontaneous locomotion, while uridine-treated mice maintained a significantly higher level of activity (longer total distance traveled 3761.7 ± 789.1 cm vs. 2477.5 ± 1017.6 cm in DM+; p = 0.023). Electrophysiological evaluation revealed near-normal sciatic nerve function in DM+U mice, including higher compound motor action potential (CMAP) amplitudes (10.21 ± 0.64 mV vs. 5.75 ± 0.72 mV; p < 0.0001) and reduced F-wave latency (6.35 ± 0.45 ms vs. 7.29 ± 0.31 ms; p < 0.0001). Histological and immunohistochemical analyses (PGP 9.5) further confirmed reduced nerve degeneration in DM+U mice. Our data suggest that chronic uridine administration may confer both functional and structural neuroprotection in diabetic neuropathy, even in the absence of improved glycemic control.