prosaptide and Disease-Models--Animal

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) after 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.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Rats; Rats, Sprague-Dawley; Saposins; Time Factors

We have previously demonstrated that the prosaposin-derived 14-mer peptide TX14(A) prevents structural and functional abnormalities associated with peripheral neuropathy in diabetic rats. Unusually, this neuroprotective peptide also exhibited acute anti-hyperalgesic properties in the same model, suggesting a dual action of TX14(A) that could allow therapeutic targeting of both degenerative neuropathy and neuropathic pain. In the present study, we have extended investigation of the anti-allodynic properties of TX14(A) to a range of models in which allodynia is induced using metabolic, physical, neurotoxic or chemical/inflammatory damage to the peripheral nerve. Single systemic doses of TX14(A) rapidly alleviated tactile allodynia in rats in which nerve injury was induced by diabetes, sciatic nerve hemiligation, systemic paclitaxel treatment or paw formalin injection. Further, TX14(A) pre-treatment prevented onset of allodynia in the paclitaxel and formalin injection models. These results indicate that TX14(A) has anti-allodynic properties in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for a wide range of peripheral neuropathies and neuropathic pain states.

Topics: Analgesics, Non-Narcotic; Analysis of Variance; Animals; Diabetes Complications; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Nerve Growth Factors; Paclitaxel; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Sciatica; Skin; Time Factors