Beneficial actions of neurotrophic factors on diabetes-induced peripheral neuropathy

Neurotrophic factors are vital for proper development and maintenance of sensory neurons. Postnatally, small neurons that transmit pain and temperature information are responsive to either nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF). Neurotrophin-3 (NT-3) is responsible for postnatal maintenance of select large mechanosensitive neurons. Neurotrophic support is often disrupted following axonal injury or disease, potentially contributing to subsequent peripheral nerve damage. In diabetes mellitis, approximately 50% of patients suffering from long-standing hyperglycemia will develop peripheral nerve damage known as diabetic neuropathy (DN). Distal extremities are preferentially affected, resulting in a decreased ability to perceive cutaneous sensations, including touch, vibration, temperature and pain. Deficient neurotrophic support has been strongly implicated in the development and maintenance of DN.; To evaluate the role of neurotrophins in DN, studies were carried out in mice rendered hyperglycemic by streptozotocin (STZ). Diabetic mice had significantly reduced cutaneous innervation in both flank and footpad skin. Distal cutaneous axon loss was present in all sensory populations, including those responsive to NGF, GDNF and NT-3. Diabetic mice also displayed significantly reduced behavioral responses to cutaneous mechanical stimuli and nocifensive responses to formalin injection were significantly reduced during both acute and inflammatory phases.; To evaluate whether neurotrophin treatment could normalize anatomical and behavioral deficits, diabetic mice were treated intrathecally with neurotrophic factors. NGF treatment stimulated axon branching and significantly restored behavioral responses of diabetic mice to mechanical and chemogenic stimuli. GDNF treatment increased both cutaneous innervation and axon branching and also restored chemogenic sensitivity. NT-3 treatment significantly improved the innervation of myelinated fibers in the footpad of diabetic mice, but did not significantly affect behavioral responses to either mechanical or chemogenic stimuli.; These results reveal that, similar to human diabetic patients, STZ-induced diabetic mice have significantly reduced cutaneous innervation and sensitivity. Intrathecal treatment using specific neurotrophins significantly stimulates cutaneous axon growth and branching and restores behavioral responses to mechanical and chemogenic stimuli. Together, these data strongly suggest that DRG neurons in diabetic mice are responsive to treatment with neurotrophins, which may prove to be powerful therapeutic agents for the treatment of human DN.