Study On The Effects Of Nerve Growth Factor And Aldose Reductase Inhibitor On The Pathogenesis Of Diabetic Neuropathy

DNP, which not only constitutes a major cause for mortality but also interferes with the lives of the patients, is one of the most frequent complications of DM. It is reported the prevalence rate of DNP in DM patients is about 30-40%. The extent of chronic hyperglycemia progresses and the duration of DM are risk factors of DNP, which affects sensory, motor and autonomic peripheral nerves, especially the sensory ones. The experiments with diabetic models of rats show a decrease in NCV similar to that observed in human diabetes. The morphological changes include degeneration, loss, regeneration of myelinated nerve libers accompanied by segmental demyelination and remyelination, degeneration and regeneration of unmyelinated nerve fibers and microangiopathy.The role of NGF in pathogenesis of DNP has been noted recently. SP and CGRP, which mediate the sense of pain, are two neuropeptides modulatd by NGF. It has been reported that ARI promotes the expression and/or secretion of NGF into the culture medium. In the present study, 46 male Wistar rats were randomly divided into five groups, one was saved as healthy control, and the others were intravenously injected STZ to make DM models. After 15 weeks, one injected group was saved as DM control, the other three groups were treated with NGF, ARI Epalrestat and insulin for 6 weeks, respectively. The tailflick threshold (a method to assess the rats response to a thermal noxious stimulus ), the electrophysiological examination of peripheral nerve including MNCV, SNCV, the latency and amplitude of M potential and H reflex were obtained, especially the latency of H reflex for it can reflect the validity of immatured diabetic rats more objectively. The ultrastructural changes and the number of myelinated fibers in sural nerve were also observed. With immunohistochemistry and ELISA, the percentage of SP, CGRP immunopositive cells in cervical 5 DRG and the content of NGF in serum and sciatic nerve were measured to assess the role of NGF and the related peptides in the pathogenesis of DNP and the effects of different treatments.The hyperglycemia, HbA1c-raising, bodyweight-losing, over-eating, over-drinking and polyiria developed in STZ-treated rats, indicating the success of the model. The tailflick threshold elevated, the MNCV, the SNCV and the amplitude reduced, the latency prolonged. Marked degeneration of myelin and Wallerian degeneration could be observed, though without changes in the number of myelinated nerve fibers. The drop of the percentage of SP, CGRP immunopositive cells and the content of NGF implies that the lackness of NGF through the subsequent effects on neuropeptides plays a role in the pathogenesis of DNP. The tailflick threshold and the amplitude of M potential and H reflex were significantly improved after all treatments, so were the MNCV, the SNCV and the latency after ARI treatment. However, treatments with NGF and insulin resulted in only a partial improvement Since NGF acts mainly on small unmyelinated fiber DRG sensory neurons, the amplitude which reflects the function of axon was increased, but the NCV which reflects the function of myelin was not ameliorated. DNP should be treated earlier before the presence of morphological changes. NGF and ARI treatment can significantly increase the percentage of SP, CGRP immunopositive cells and the content of NGF, indicating exogenous NGF can get to its sensitve neurons and exert physiological function ARI can promote the production and/or secretion of endogenous NGF. However, SC is the primary intrafascicular location for ARI, which not only inhibits the accumulation of sorbitol and the reduction of the activity of Na*-K*-ATPase but also improves the blood flow of nerves. The improvement on NGF reduction after insulin treatment may attribute to the structural similarity between NGF and insulin. The incompleteness of each treatment illustrates the roles of multifactor in the pathogenesis of DNP. Increasing the dosage and the duration of NGF treatment, prevention earlier and combined treatment should b...