Ciliary neurotrophic factor (CNTF) protein and bioactivity are reduced in the peripheral nerve of hyperglycemic rats with a cause related to metabolism of hexose sugars by aldose reductase. Here the efficacy of CNTF treatment against disorders of nerve function in hyperglycemic rats was investigated. CNTF treatment from the onset of 8 weeks of galactose feeding prevented nerve conduction slowing in a dose-dependent manner. Streptozotocin-induced diabetic rats were maintained for 4 weeks before CNTF treatment was initiated. Four weeks of CNTF treatment significantly improved nerve conduction compared with untreated diabetic rats and also normalized the recovery of toe spread after sciatic nerve crush. One week of CNTF treatment significantly improved the distance of sensory nerve regeneration achieved after nerve crush injury compared with untreated diabetic rats. CNTF was without effects on any parameter in nondiabetic rats. Eight weeks of diabetes did not impair macrophage recruitment 1 and 7 days after nerve crush; neither did intraneural injections of CNTF and CNTFR␣ enhance recruitment in diabetic or control rats. These observations point to the potential utility of CNTF in treating nerve dysfunction in experimental diabetes.

Prosaposin is both a precursor of sphingolipid activator proteins and a secreted neurotrophic and myelinotrophic factor. Because peripheral nerve regeneration is impaired in diabetes mellitus, we measured prosaposin protein levels from control and streptozotocin-diabetic rats by collecting endoneurial fluid secreted into a bridging tube connecting the ends of transected sciatic nerve. Prosaposin protein levels were significantly reduced in endoneurial fluid from diabetic rats and increased in the proximal nerve stump compared to controls. To investigate whether a prosaposin-derived peptide could improve nerve regeneration, rats were treated with prosaptide TX14(A) following sciatic nerve crush. In control rats, TX14(A) was without effect in the uninjured nerve but shortened toe spread recovery time after nerve crush. In diabetic rats, efficacy of prosaptide TX14(A) was confirmed by correction of thermal hypoalgesia, formalin-evoked hyperalgesia and conduction slowing in the uninjured nerve. The peptide also prevented diabetes-induced abnormalities in nerve regeneration distance and mean axonal diameter of regenerated axons, whereas delayed recovery of toe spread was not improved. Muscle denervation atrophy was attenuated by TX14(A) in both control and diabetic rats. These results suggest that reduced prosaposin secretion after nerve injury may contribute to impaired regeneration rates in diabetic rats and that prosaptide TX14(A) can improve aspects of nerve regeneration.