Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy.

Hedgehog proteins modulate development and patterning of the embryonic nervous system. As expression of desert hedgehog and the hedgehog receptor, patched-1, persist in the postnatal and adult peripheral nerves, the hedgehog pathway may have a role in maturation and maintenance of the peripheral nervous system in normal and disease states. We measured desert hedgehog expression in the peripheral nerve of maturing diabetic rats and found that diabetes caused a significant reduction in desert hedgehog mRNA. Treating diabetic rats with a sonic hedgehog-IgG fusion protein fully restored motor- and sensory-nerve conduction velocities and maintained the axonal caliber of large myelinated fibers. Diabetes-induced deficits in retrograde transport of nerve growth factor and sciatic-nerve levels of calcitonin gene-related product and neuropeptide Y were also ameliorated by treatment with the sonic hedgehog-IgG fusion protein, as was thermal hypoalgesia in the paw. These studies implicate disruption of normal hedgehog function in the etiology of diabetes-induced peripheral-nerve dysfunction and indicate that delivery of exogenous hedgehog proteins may have therapeutic potential for the treatment of diabetic neuropathy.

Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy: interactions with aldose reductase.

This study examined the role of p38 mitogen-activated protein (MAP) kinase in transducing high glucose into deficits in nerve conduction velocity (NCV) that are characteristic of diabetic neuropathy. p38 activation and NCV were measured in streptozocin-induced diabetic rats treated with a p38 inhibitor, an aldose reductase inhibitor, and insulin. Dorsal root ganglia (DRG) from diabetic animals showed marked activation of p38 at 12 weeks of diabetes. Insulin treatment for the last 4 of 12 weeks of diabetes normalized p38 activation. Furthermore, activation was completely prevented by 12 weeks' treatment with the aldose reductase inhibitor, fidarestat. Immunocytochemistry localized activation of p38 to the nuclei of virtually all sensory neuronal phenotypes in the DRG, and activation was clear in diabetes, as was inhibition by fidarestat and by the p38 inhibitor SB 239063. In the ventral horn of the spinal cord, p38 was present in motoneuron cell bodies; and again, activation in diabetes and fidarestat inhibition was clear. Treatment of diabetic animals with a specific inhibitor of p38 (SB 239063), fidarestat, or insulin also prevented reductions in both motor and sensory NCV. These findings suggest that increased polyol pathway flux in diabetic animals leads to the activation of p38. This activation can mediate changes in gene transcription and cellular phenotype that are likely to underlie the NCV deficits. Insulin and aldose reductase inhibitors can prevent excess polyol pathway flux, and hence these agents may prevent NCV deficits by preventing p38 MAP kinase activation.

Neurotrophin-3 prevents the proximal accumulation of neurofilament proteins in sensory neurons of streptozocin-induced diabetic rats.

The relation between neurofilament expression and/or phosphorylation in the proximal versus distal components of the sensory peripheral neuraxis was studied and related to disorders in structure and function of the distal axon of streptozocin (STZ)-induced diabetic rats studied for 14 weeks. The ability of neurotrophin-3 (NT-3) to prevent abnormalities in neurofilament biology was also investigated. Compared with age-matched controls, neurofilament heavy (NF-H) (3.3-fold) and neurofilament medium (NF-M) (2.5-fold), but not neurofilament light (NF-L), subunits accumulated in the proximal axon of sensory neurons of the lumbar dorsal root ganglia (DRG) in untreated diabetic rats. Neurofilament accumulation was prevented by NT-3. Small- and large-diameter sensory neurons exhibited elevated levels of NF-H protein accumulation and phosphorylation in the DRG of untreated diabetic rats, levels that were ameliorated by NT-3. The sural nerve of untreated diabetic rats showed a 50% decrease in the levels of NF-H and NF-M, but not NF-L, subunits; NT-3 only partially normalized the defect in NF-M expression. These observations were associated with significant lowering of motor and sensory nerve conduction velocity but no alteration in the mean axonal diameter of myelinated axons in the sural nerve in untreated diabetic rats. It is proposed that the accumulation of NF-H and NF-M subunits in the proximal axon is an etiologic factor in the distal axon degeneration observed in diabetes.